Introduction of alkyl substituents to aromatic compounds

ABSTRACT

Novel selective synthesis route to introduce primary alkyl groups on aromatic compounds is disclosed. The synthesis route is based on electrophilic aromatic substitutions of thionium ion species that are generated in-situ from aldehydes and thiols, affording benzyl sulfide that can be reduced with triethylsilane.

RELATED APPLICATIONS

This application is a National Phase of PCT Patent Application No.PCT/IL2016/050182 having International filing date of Feb. 16, 2016,which claims the benefit of priority from U.S. Patent Application No.62/116,595, filed on Feb. 16, 2015. The contents of the aboveapplications are all incorporated by reference as if fully set forthherein in their entirety.

FIELD OF THE INVENTION

The present invention, in some embodiments thereof, relates to a novelsynthesis route of electrophilic aromatic substitution and, moreparticularly, but not exclusively, to introducing alkyl groups toaromatic compounds.

BACKGROUND OF THE INVENTION

Aromatic and heteroaromatic substructure are among the most importantstructural motifs abundant in organic molecules. The Friedel-Craftsalkylation [Olah, G. A. Friedel-crafts chemistry. Wiley New York: 1973],one of the oldest known chemical transformations, is the preferredmethod for introducing alkyl substituents, derived from alkyl halides,onto aromatic compounds [Rueping, M. et al. Org. Chem. 2010, 6, 6.].Over the years, the classic methods have seen improvements andtechniques that are less destructive, non-toxic and have higherselectivity [Mertins, K. et al, Angewandte Chemie International Edition2005, 44, 238] were developed.

While this method is reliable for installation of benzyl groups andsecondary and tertiary alkyl moieties [Sawama, Y. et al., Chemistry—AEuropean Journal 2014, 20, 510], the major limitation of the reactionlies in the fact that it is unsuitable for primary alkyl halides. Thelatter react less readily, therefore require harsh conditions [Smith, M.B.; March, J., March's Advanced Organic Chemistry: Reactions,Mechanisms, and Structure. Wiley: 2007; Carey, F. A.; Sundberg, R. J.,Advanced Organic Chemistry: Part A: Structure and Mechanisms. Springer:2007], and result in a mixture of rearrangement products. Other majordrawbacks, such as polyalkylation of the aromatic core, and therequirement for strict anhydrous conditions, further affect theapplicability of the process. To overtake the synthetic difficulties ofplacing primary alkyl groups onto aromatic compounds, alternativemulti-step protocols have been developed, such as Friedel-Craftsacylation and reduction, reductive Friedel-Crafts alkylation [suchimoto,T et al., Chemical Communications 1996, 2345], metal catalyzedcross-coupling [Hatakeyama, T. et al. J. Am. Chem. Soc. 2010, 132,10674; González-Bobes, F., Fu, G. C. J. Am. Chem. Soc. 2006, 128, 5360;Molander, G. A. et al. Org. Lett. 2010, 12, 5783; Yang, C. T. et al.,Angew. Chem. Int. Ed. 2011, 50, 3904. Li, C. et al, Angewandte ChemieInternational Edition 2015], and metal catalyzed C—H activation [Bair,J. S. et al., J. Am. Chem. Soc. 2014, 136, 13098; Robbins, D. W.;Hartwig, J. F. Angew. Chem. Int. Ed. 2013, 52, 933].

SUMMARY OF THE INVENTION

The present invention, in some embodiments thereof, relates to a novelsynthesis route of electrophilic aromatic substitution and, moreparticularly, but not exclusively, to introducing alkyl groups toaromatic compounds.

According to an aspect of some embodiments of the present invention,there is provided a process for synthesis of a compound represented byFormula I:

the process comprising:

reacting a compound represented by Formula II:

with a compound represented by Formula III:

and with R₃SH

in the presence of an acidic catalyst and a suitable solvent, wherein:

R₁ is alkyl or aryl;

R₂ represents 0 to 5 substituents, wherein, in each occurrence, eachsubstituent is independently selected from the group consisting of:alkyl, alkenyl, alkynyl, cycloalkyl, heteroalicyclic, aryl, heteroaryl,hydroxy, alkoxy, aryloxy, thiohydroxy, thioalkoxy, thioaryloxy, halide,amine, amide, carbonyl, thiocarbonyl, carboxy, thiocarboxy, epoxide,sulfonate, sulfonyl, sulfinyl, sulfonamide, nitro, nitrile, isonitrile,thiirane, aziridine, nitroso, hydrazine, sulfate, azide, phosphonyl,phosphinyl, urea, thiourea, carbamyl and thiocarbamyl, fused ring systemcontaining up to three 6-member carbocyclic, each being substituted ornon-substituted;

R₃ is selected from alkyl, aryl (e.g., phenyl), alkoxy, aryloxy,carbonyl, carboxy, substituted or non-substituted; and

R₄, R₅, and R₆ are each independently selected from the group consistingof: hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heteroalicyclic,aryl, heteroaryl, hydroxy, alkoxy, aryloxy, thiohydroxy, thioalkoxy,thioaryloxy, halide, amine, amide, carbonyl, thiocarbonyl, carboxy,thiocarboxy, epoxide, sulfonate, sulfonyl, sulfinyl, sulfonamide, nitro,nitrile, isonitrile, thiirane, aziridine, nitroso, hydrazine, sulfate,azide, phosphonyl, phosphinyl, urea, thiourea, carbamyl andthiocarbamyl,

thereby forming said compound represented by Formula I.

In some embodiments, R₃ is ethyl.

In some embodiments, the acidic catalyst is one or more Lewis acidsselected from the group consisting of: CuCl₂, Sc(OTf)₃, Fe(OTf)₃,In(OTf)₃, BF3.OEt₂, and Cu(OTf)₂.

In some embodiments, the acidic catalyst is or comprises one or moreBrønsted acids selected from Triflic acid (TfOH), para-toluenesulfonicacid, and trifluoroacetic acid.

In some embodiments, the suitable solvent is a polar solvent selectedfrom the group consisting of: acetonitrile, nitromethane, and2,2,2-trifluoroethanol (TFE), hexafluoroisopropanol (HFIP) or a mixturethereof.

In some embodiments, the process is characterized by at least 30% yieldof the compound.

According to an aspect of some embodiments of the present invention,there is provided a product represented by Formula I:

obtained by the process as disclosed herein, wherein R₁-R₆ are definedhereinabove.

In some embodiments, the product represented by Formula I has theFormula I1:

or Formula I2:

or Formula I3:

or Formula I4:

or Formula I5:

or Formula I6:

or Formula I7:

or Formula I8:

or Formula I9:

or Formula I10:

or Formula I11:

or Formula I12:

or Formula I13:

or Formula I14:

or Formula I15:

or Formula I16:

or Formula I17:

or Formula I18:

or Formula I19:

or Formula I20:

or Formula I21:

or Formula I22:

or Formula I23:

or Formula I24:

or Formula I25:

or Formula I26:

or Formula I27:

or Formula I28:

or Formula I29:

or Formula I30:

or Formula I31:

or Formula I32:

or Formula I33:

In some embodiments, the process further comprises a subsequent step ofreacting the compound represented by Formula I with a reducing agent,thereby forming the compound represented by Formula IV:

wherein R1-R6 are defined hereinabove.

In some embodiments, the reducing agent is a silane. In someembodiments, the silane is Et₃SiH.

In some embodiments, there is provided a product represented by FormulaIV obtained following a subsequent step of reacting the compoundrepresented by Formula I with a reducing agent. In some embodiments, theproduct represented by Formula IV has the Formula IV1:

or Formula IV2:

or Formula IV3:

or Formula IV4:

or Formula IV5:

or Formula IV6:

or Formula IV7:

or Formula IV8:

or Formula IV9:

or Formula IV10:

or Formula IV11:

or Formula IV12:

or Formula IV13:

or Formula IV14:

In some embodiments, there is provided a pharmaceutical compositioncomprising the product obtained by the disclosed process and representedby Formula IV and a pharmaceutically acceptable excipient.

In some embodiments, there is provided a composition comprising:

(i) one or more Lewis acids selected from the group consisting of:CuCl₂, Sc(OTf)₃, Fe(OTf)₃, In(OTf)₃, BF₃.OEt₂, TfOH and Cu(OTf)₂;

(ii) a polar solvent selected from the group consisting of:acetonitrile, nitromethane, and 2,2,2-trifluoroethanol (TFE), or amixture thereof; and

(iii) RSH, wherein R is selected from the group consisting of: alkyl,benzyl, alkoxy, aryloxy, carbonyl, carboxy, substituted ornon-substituted.

In some embodiments, the Lewis acid is in a molar concentration of atleast 1%. In some embodiments, the polar solvent is TFE.

In some embodiments, there is provided a use of a product of formula Iand/or a product of formula IV obtained by a process disclosed hereinfor the preparation of a pharmaceutical composition.

BRIEF DESCRIPTION OF THE DRAWINGS

Some embodiments of the invention are herein described, by way ofexample only, with reference to the accompanying drawings. With specificreference now to the drawings in detail, it is stressed that theparticulars shown are by way of example and for purposes of illustrativediscussion of embodiments of the invention. In this regard, thedescription taken with the drawings makes apparent to those skilled inthe art how embodiments of the invention may be practiced.

In the drawings:

FIGS. 1A-B present Scheme 1A showing a classic Friedel-Craft alkylation(FIG. 1A), and Scheme 1B showing the process of the present invention,in some embodiments thereof (FIG. 1B).

DETAILED DESCRIPTION

The present invention, in some embodiments thereof, relates to asynthesis route of electrophilic aromatic substitution and, moreparticularly, but not exclusively, to introducing alkyl groups on one ormore aromatic compounds.

Before explaining at least one embodiment of the invention in detail, itis to be understood that the invention is not necessarily limited in itsapplication to the details set forth in the following description orexemplified by the Examples. The invention is capable of otherembodiments or of being practiced or carried out in various ways.

As discussed hereinabove, currently known methodologies of introducingprimary alkyl groups on aromatic compounds is a difficult task toachieve. A major limitation lies in the fact that it is unsuitable forprimary alkyl halides. The latter react less readily, therefore requireharsh conditions and result in a mixture of rearrangement products.

Moreover, the tendency of aliphatic aldehydes to dimerize under acidicconditions prevents the ability to apply them in aromatic electrophilicreactions.

The present invention is based in part on the surprising finding that ahighly selective method may be employed for introducing alkyl groups,and particularly, primary alkyl groups on aromatic compounds. Thesynthesis route is, in some embodiments, is one-pot“Pummerer/Friedel-Crafts” alkylation. In some embodiments, this one-potalkylation is based on electrophilic aromatic substitution(s) ofthionium ion species that is generated in-situ from aldehyde(s) andthiol(s), affording aryl sulfide. Aryl sulfide can be then reduced withtriethylsilane. In some embodiments, this one-pot alkylation is suitablefor aromatic compounds and both linear and branched aliphatic aldehydes.In some embodiments, the alkylation is performed under air and in thepresence of water and various functional groups.

In some embodiments, the disclosed reaction is compatible with a varietyof functionalities and reagents (including, without limitation, alkylhalides, which are the substrates of the classic Friedel-Craftsreaction). In some embodiments, the disclosed reaction is watertolerant. In some embodiments, the disclosed reaction avoids the use ofcorrosive reagents and toxic halides, and can be applied to keybiologically active compounds.

The Process:

According to some aspects, the present invention provides a process forsynthesis of a compound represented by Formula I (designated as:“compound I”):

In some embodiments, the process comprises:

reacting a compound represented by Formula II (designated as: “compoundII” and also referred to as “the aldehyde”):

with a compound represented by Formula III (designated as: “compoundIII”):

and with R₃SH, wherein:

R₁ is alkyl or aryl;

R₂ represents 0 to 5 substituents, wherein, in each occurrence, eachsubstituent is independently selected from the group consisting of:alkyl, alkenyl, alkynyl, cycloalkyl, heteroalicyclic, aryl, heteroaryl,hydroxy, alkoxy, aryloxy, thiohydroxy, thioalkoxy, thioaryloxy, halide,amine, amide, carbonyl, thiocarbonyl, carboxy, thiocarboxy, epoxide,sulfonate, sulfonyl, sulfinyl, sulfonamide, nitro, nitrile, isonitrile,thiirane, aziridine, nitroso, hydrazine, sulfate, azide, phosphonyl,phosphinyl, urea, thiourea, carbamyl and thiocarbamyl, fused ring systemcontaining up to three 6-member carbocyclic, each being substituted ornon-substituted;

R₃ is selected from alkyl, aryl (e.g., phenyl), alkoxy, aryloxy,carbonyl, carboxy, substituted or non-substituted;

R₄, R₅, and R₆ are each, independently, selected from the groupconsisting of: hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl,heteroalicyclic, aryl, heteroaryl, hydroxy, alkoxy, aryloxy,thiohydroxy, thioalkoxy, thioaryloxy, halide, amine, amide, carbonyl,thiocarbonyl, carboxy, thiocarboxy, epoxide, sulfonate, sulfonyl,sulfinyl, sulfonamide, nitro, nitrile, isonitrile, thiirane, aziridine,nitroso, hydrazine, sulfate, azide, phosphonyl, phosphinyl, urea,thiourea, carbamyl and thiocarbamyl, to thereby form the compoundrepresented by Formula I.

In some embodiments, the process is performed in the presence of anacidic catalyst and/or in a suitable solvent.

As used herein and in the art, the term “catalyst” refers to a substancewhich initiates or accelerates a chemical reaction.

In some embodiments, the acidic catalyst is one or more Lewis acids. Asused herein and in the art, “Lewis acid” refers to a powerful electronpair acceptor.

Exemplary Lewis acids include, but are not limited to, CuCl₂, Sc(OTf)₃,Fe(OTf)₃, In(OTf)₃, BF₃.OEt₂, and Cu(OTf)₂.

In some embodiments, the acidic catalyst is or comprises one or moreBrønsted acids.

As used herein and in the art, “Brønsted acid” refers to a compound thatis capable of donating a proton (H⁺) to another compound. ExemplaryBrønsted acids include, but are not limited to, Triflic acid (TfOH),para-toluenesulfonic acid, and trifluoroacetic acid.

In some embodiment, the reaction process is performed in a mild acidiccondition. By “mild acidic condition” it is meant that the molarconcentration of the acid in the solvent is e.g., about 0.25%, about0.5%, about 1.75%, about 2%, about 2.25%, about 2.5%, about 2.75%, about3%, about 3.25%, about 3.5%, about 3.75%, about 4%, about 4.25%, about4.5%, about 4.75%, about 5%, about 5.25%, about 5.5%, about 5.75%, about6%, about 6.25%, about 6.5%, about 6.75%, about 7%, about 7.25%, about7.5%, about 7.75%, about 8%, about 8.25%, about 8.5%, about 8.75%, about9%, about 9.25%, about 9.5%, about 9.75%, or about 10%, including anyvalue and range therebetween. Each possibility represents a separateembodiment of the present invention.

In some embodiments, the process (i.e. the synthesis procedure) isperformed at a temperature that ranges from 10° C. to 90° C. In someembodiments, the reaction process is performed at a temperature thatranges from 20° C. to 70° C., or e.g., from 25° C. to 45° C., or from30° C. to 50° C.

In some embodiments, the reaction time is at least 1 minute. In someembodiments, the reaction time is e.g., at least 5 minutes, at least 10minutes, at least 15 minutes, at least 20 minutes, at least 25 minutes,at least 30 minutes, at least 35 minutes, at least 40 minutes, at least45 minutes, at least 50 minutes, at least 55 minutes, at least 60minutes, at least 65 minutes, at least 70 minutes, at least 75 minutes,or at least 80 minutes. Each possibility represents a separateembodiment of the present invention.

In some embodiments, the reaction time is at least 1 hour. In someembodiments, the reaction time is e.g., at least 2 hours, at least 3hours, at least 4 hours, at least 5 hours, at least 6 hours, at least 7hours, at least 8 hours, at least 9 hours, at least 10 hours, at least11 hours, at least 12 hours, at least 13 hours, at least 14 hours, atleast 15 hours, at least 16 hours, at least 17 hours, at least 18 hours,at least 19 hours, at least 20 hours, at least 21 hours, at least 22hours, at least 23 hours, or at least 24 hours. Each possibilityrepresents a separate embodiment of the present invention.

It is noteworthy that contrary to the classic Friedel-Crafts alkylation,which requires anhydrous conditions, the electrophilic aromaticsubstitution underlying the synthesis route disclosed hereinthroughoutcan be carried out in water, as exemplified in the Example section.

In some embodiments, the synthesis route disclosed hereinthroughoutenables mono-substitution of the alkyl scaffold to an aromatic compound.In some embodiments, the alkyl scaffold maintains its originalstructure.

An exemplary embodiment of the synthesis route of the invention isdescribed in the Examples section below.

It is also of note that the aldehyde (e.g., compound II) in thesynthesis route disclosed herein may be either linear or branched.

In some embodiments the synthesis route disclosed hereinthroughout ischaracterized by a yield of e.g., about 10%, about 20%, about 30%, about40%, about 50%, about 60%, about 70%, about 80%, about 90%, about 100%,including any value and range therebetween, based on the initial molarof the arene.

In some embodiment, the suitable solvent is a polar solvent. By “polarsolvent”, it is meant to include any solvent that exhibits polar forceson solutes, due to high dipole moment, wide separation of charges, ortight association.

Exemplary polar solvents include, but are not limited to, acetonitrile,nitromethane, and 2,2,2-trifluoroethanol (TFE), nitrobenzene,hexa-fluoro-isopropanol (HFIP) or a mixture thereof.

Without being bound by any particular theory, it is assumed that thedisclosed synthesis route is based on electrophilic aromaticsubstitutions of thionium ion species, transformed from aldehydes andthiols under the acid-catalyzed conditions, as described hereinbelow inthe Example section. This transformation affords e.g.,1-(ethylthio)benzyl and alkylarenes in high chemo- and regioselectivity,which can be reduced e.g., in situ, to the corresponding saturated alkylarenes, as summarizes in Scheme 1B in the Example section.

In some embodiments, the R₂ substituent is absent. In some embodiments,R₂ represents one substituent of alkyl. In some embodiments, R₂represents two substituents of alkyl. In some embodiments, R₂ representsthree substituents of alkyl.

In some embodiments, R₂ represents one substituent of ethoxy. In someembodiments, R₂ represents two substituents of ethoxy. In someembodiments, R₂ represents three substituents of ethoxy.

In some embodiments, R₂ is one substituent of 4-methoxy (“4-OMe”; hereinthe “number-” represents the position in respects to the thiol group inthe compound of the product represented by Formula I)). In someembodiments, R₂ represents one substituent of 4-SMe. In someembodiments, R₂ represents two substituents of 2,5-di-OMe. In someembodiments, R₂ represents three substituents of 2,4,6-tri-Me. In someembodiments, R₂ represents three substituents of 2,4,6-tri-OMe. In someembodiments, R₂ represents 2-naphthalene fused at position 2.

In some embodiments, R₃ is ethyl. In some embodiments, R₃ is isopropyl(iPr). In some embodiments, R₃ is benzyl (Bn). In some embodiments, R₃is acyl (carbonyl).

In some embodiments, R₁ is alkyl, substituted or non-substituted. Insome embodiments, R₁ is methyl. In some embodiments, R₁ is aryl. In someembodiments, R₁ is bulky, for example, branched alkyl, branched alkenylor branched alkynyl and/or a cyclic moiety. In some embodiments, thebulky moiety is a cyclic moiety selected from the group consisting ofcycloalkyl, heteroalicyclic, aryl and heteroaryl, each being substitutedor non-substituted.

In some embodiments, one or more (e.g., two) of R₄, R₅ and R₆ groups areeach independently selected from the group consisting of: hydrogen,alkyl, alkenyl, alkynyl, cycloalkyl, heteroalicyclic, aryl, heteroaryl,hydroxy, alkoxy, aryloxy, thiohydroxy, thioalkoxy, thioaryloxy, halide,amine, amide, carbonyl, thiocarbonyl, carboxy, thiocarboxy, epoxide,sulfonate, sulfonyl, sulfinyl, sulfonamide, nitro, nitrile, isonitrile,thiirane, aziridine, nitroso, hydrazine, sulfate, azide, phosphonyl,phosphinyl, urea, thiourea, carbamyl and thiocarbamyl, a fused ringsystem containing up to three 6-member carbocyclic, each beingsubstituted or non-substituted.

In some embodiments, one or more (e.g., two) of R₄, R₅ and R₆ groups arehydrogen atoms. In some embodiments, two of R₄, R₅ and R₆ groups arehydrogen atoms. In some embodiments, two of R₄, R₅ and R₆ groups arehydrogen atoms and one of R₄, R₅ and R₆ groups are selected from:hydroxyl, —CO₂H, —CN, —OMe, halide, —CN, —NMe₂. In some embodiments, thehalide is bromide.

In some embodiments, the synthesis is performed such that the molarratio of R₃SH and compound II at the beginning of the reaction is e.g.,1:1, 1:2, 1:3, 1:4, 1:5, 1:6, 1:7, 1:8, 1:9, 1:10, including any valuetherebetween. Each possibility represents a separate embodiment of thepresent invention.

In exemplary embodiments, the molar ratio of R₃SH and compound II at thebeginning of the reaction is 1:2, respectively. In additional exemplaryembodiments, the molar ratio of R₃SH and compound II at the beginning ofthe reaction is 1:3, respectively.

In some embodiments, the synthesis is performed such that the molarratio of compound III and compound II is e.g., 1:1, 1:2, 1:3, 1:4, 1:5,1:6, 1:7, 1:8, 1:9, or 1:10, including any value therebetween. Inexemplary embodiments, the molar ratio is about 1:2.

In some embodiments, the present invention provides a process for thepreparation of a compound of formula I1:

In some embodiments, the present invention provides a process for thepreparation of a compound of formula I2:

In some embodiments, the present invention provides a process for thepreparation of a compound of formula I3:

In some embodiments, the present invention provides a process for thepreparation of a compound of formula I4:

In some embodiments, the present invention provides a process for thepreparation of a compound of formula I5:

In some embodiments, the present invention provides a process for thepreparation of a compound of formula I6:

In some embodiments, the present invention provides a process for thepreparation of a compound of formula I7:

In some embodiments, the present invention provides a process for thepreparation of a compound of formula I8:

In some embodiments, the present invention provides a process for thepreparation of a compound of formula I9:

In some embodiments, the present invention provides a process for thepreparation of a compound of formula I10:

In some embodiments, the present invention provides a process for thepreparation of a compound of formula I11:

In some embodiments, the present invention provides a process for thepreparation of a compound of formula I12:

In some embodiments, the present invention provides a process for thepreparation of a compound of formula I13:

In some embodiments, the present invention provides a process for thepreparation of a compound of formula I14:

In some embodiments, the present invention provides a process for thepreparation of a compound of formula I15:

In some embodiments, the present invention provides a process for thepreparation of a compound of formula I16:

In some embodiments, the present invention provides a process for thepreparation of a compound of formula I17:

In some embodiments, the present invention provides a process for thepreparation of a compound of formula I18:

In some embodiments, the present invention provides a process for thepreparation of a compound of formula I19:

In some embodiments, the present invention provides a process for thepreparation of a compound of formula I20:

In some embodiments, the present invention provides a process for thepreparation of a compound of formula I21:

In some embodiments, the present invention provides a process for thepreparation of a compound of formula I22:

In some embodiments, the present invention provides a process for thepreparation of a compound of formula I23:

In some embodiments, the present invention provides a process for thepreparation of a compound of formula I24:

In some embodiments, the present invention provides a process for thepreparation of a compound of formula I25:

In some embodiments, the present invention provides a process for thepreparation of a compound of formula I26:

In some embodiments, the present invention provides a process for thepreparation of a compound of formula I27:

In some embodiments, the present invention provides a process for thepreparation of a compound of formula I28:

In some embodiments, the present invention provides a process for thepreparation of a compound of formula I29:

In some embodiments, the present invention provides a process for thepreparation of a compound of formula I30:

In some embodiments, the present invention provides a process for thepreparation of a compound of formula I31:

In some embodiments, the present invention provides a process for thepreparation of a compound of formula I32:

In some embodiments, the present invention provides a process for thepreparation of a compound of formula I33:

In some embodiments, the synthesis further comprises a subsequent stepof oxidation or a step of reduction of the sulfide of compoundrepresented by Formula I.

In some embodiments, the subsequent step is reduction of the sulfide ofcompound represented by Formula I.

In some embodiments, the subsequent step is performed in in-situfashion.

In some embodiments, the subsequent step of reduction of the sulfidecomprises reacting the compound represented by Formula I, with one ormore reducing agents (also referred to as: “reduction step”), therebyforming the compound represented by Formula IV.

In some embodiments, the subsequent step of the reduction is performedin a one-pot follow-up procedure.

The term “one-pot”, as used herein, refers to a process for preparing adesired product, comprising simultaneously or successively adding allreactants into a reactor to have them react together, in which noseparation and/or purification of the intermediate formed is neededbefore the product is produced.

In some embodiments, the reducing agent is a silane. In someembodiments, the silane has the formula: (alkyl)₃SiH, wherein each alkylis independently as defined hereinthroughout. In some embodiments, thesilane is Et₃SiH.

In some embodiments, the silane has the formula: Ar₃SiH, wherein Ar isaryl (also termed: “arene”) as defined hereinthroughout.

In some embodiments, the reduction step is preformed such that compoundI, and Et₃SiH are in at molar ratio of e.g., at least 1:1, at least 1:2,at least 1:3, including any value therebetween.

In some embodiments, the subsequent step is performed in in-situfashion. In some embodiments, the subsequent step is performedstep-wise.

In some embodiments, the subsequent step is preformed in a solutioncomprising a catalyst. Exemplary catalysts are described hereinabove.

In some embodiments, the subsequent step is preformed in a solutioncomprising any polar solvent as defined hereinabove.

In exemplary embodiments, the compound represented by Formula IV,(obtained following the subsequent step) is IV1:

In exemplary embodiments, the compound represented by Formula IV is IV2:

In exemplary embodiments, the compound as represented by Formula IV isIV3:

In exemplary embodiments, the compound as represented by Formula IV isIV4:

In exemplary embodiments, the compound as represented by Formula IV isIV5:

In exemplary embodiments, the compound as represented by Formula IV isIV6:

In exemplary embodiments, the compound as represented by Formula IV isIV7:

In exemplary embodiments, the compound as represented by Formula IV isIV8:

In exemplary embodiments, the compound as represented by Formula IV isIV9:

In exemplary embodiments, the compound as represented by Formula IV isIV10:

In exemplary embodiments, the compound as represented by Formula IV isIV11:

In exemplary embodiments, the compound as represented by Formula IV isIV12:

In exemplary embodiments, the compound as represented by Formula IV isIV13:

In exemplary embodiments, the compound as represented by Formula IV isIV14:

As used herein, the term “alkyl” describes an aliphatic hydrocarbonincluding straight chain and branched chain groups. Preferably, thealkyl group has 21 to 100 carbon atoms, and more preferably 21-50 carbonatoms. Whenever a numerical range; e.g., “21-100”, is stated herein, itimplies that the group, in this case the alkyl group, may contain 21carbon atom, 22 carbon atoms, 23 carbon atoms, etc., up to and including100 carbon atoms. In the context of the present invention, a “longalkyl” is an alkyl having at least 20 carbon atoms in its main chain(the longest path of continuous covalently attached atoms). A shortalkyl therefore has 20 or less main-chain carbons. The alkyl can besubstituted or unsubstituted, as defined herein. The alkyl group may besubstituted or unsubstituted. When substituted, the substituent groupcan be, for example, cycloalkyl, alkenyl, alkynyl, aryl, heteroaryl,heteroalicyclic, halo, hydroxy, alkoxy, aryloxy, thiohydroxy,thioalkoxy, thioaryloxy, sulfinyl, sulfonyl, sulfonate, nitrile, nitro,azide, phosphonyl, phosphinyl, oxo, carbonyl, thiocarbonyl, urea,thiourea, carbamyl, N-carbamyl, O-thiocarbamyl, N-thiocarbamyl, C-amido,N-amido, C-carboxy, O-carboxy, sulfonamide, and amino, as these termsare defined herein.

The term “alkyl”, as used herein, also encompasses saturated orunsaturated hydrocarbon, hence this term further encompasses alkenyl andalkynyl.

The term “alkenyl” describes an unsaturated alkyl, as defined herein,having at least two carbon atoms and at least one carbon-carbon doublebond. The alkenyl may be substituted or unsubstituted by one or moresubstituents, as described hereinabove.

The term “alkynyl”, as defined herein, is an unsaturated alkyl having atleast two carbon atoms and at least one carbon-carbon triple bond. Thealkynyl may be substituted or unsubstituted by one or more substituents,as described hereinabove.

The term “cycloalkyl” describes an all-carbon monocyclic or fused ring(i.e., ring that shares an adjacent pair of carbon atoms) group whereone or more of the rings does not have a completely conjugatedpi-electron system. The cycloalkyl group may be substituted orunsubstituted, as indicated herein.

The term “aryl” describes an all-carbon monocyclic or fused-ringpolycyclic (i.e., rings which share adjacent pairs of carbon atoms)groups having a completely conjugated pi-electron system. The aryl groupmay be substituted or unsubstituted, as indicated herein.

The term “alkoxy” describes both an —O-alkyl and an —O-cycloalkyl group,as defined herein.

The term “aryloxy” describes an —O-aryl, as defined herein.

Each of the alkyl, cycloalkyl and aryl groups in the general formulasherein may be substituted by one or more substituents, whereby eachsubstituent group can independently be, for example, halide, alkyl,alkoxy, cycloalkyl, alkoxy, nitro, amine, hydroxyl, thiol, thioalkoxy,thiohydroxy, carboxy, amide, aryl and aryloxy, depending on thesubstituted group and its position in the molecule. Additionalsubstituents are also contemplated

The term “halide”, “halogen” or “halo” describes fluorine, chlorine,bromine or iodine.

The term “haloalkyl” describes an alkyl group as defined herein, furthersubstituted by one or more halide(s).

The term “hydroxyl” or “hydroxy” describes a —OH group.

The term “thiohydroxy” or “thiol” describes a —SH group.

The term “thioalkoxy” describes both an —S-alkyl group, and a—S-cycloalkyl group, as defined herein.

The term “thioaryloxy” describes both an —S-aryl and a —S-heteroarylgroup, as defined herein.

The term “amine” describes a —NR′R″ group, with R′ and R″ as describedherein.

The term “heteroaryl” describes a monocyclic or fused ring (i.e., ringswhich share an adjacent pair of atoms) group having in the ring(s) oneor more atoms, such as, for example, nitrogen, oxygen and sulfur and, inaddition, having a completely conjugated pi-electron system. Examples,without limitation, of heteroaryl groups include pyrrole, furane,thiophene, imidazole, oxazole, thiazole, pyrazole, pyridine, pyrimidine,quinoline, isoquinoline and purine.

The term “heteroalicyclic” or “heterocyclyl” describes a monocyclic orfused ring group having in the ring(s) one or more atoms such asnitrogen, oxygen and sulfur. The rings may also have one or more doublebonds. However, the rings do not have a completely conjugatedpi-electron system. Representative examples are piperidine, piperazine,tetrahydrofurane, tetrahydropyrane, morpholino and the like.

The term “carboxy” or “carboxylate” describes a —C(═O)—OR′ group, whereR′ is hydrogen, alkyl, cycloalkyl, alkenyl, aryl, heteroaryl (bondedthrough a ring carbon) or heteroalicyclic (bonded through a ring carbon)as defined herein.

The term “carbonyl” describes a —C(═O)—R′ group, where R′ is as definedhereinabove.

The above-terms also encompass thio-derivatives thereof (thiocarboxy andthiocarbonyl).

The term “thiocarbonyl” describes a —C(═S)—R′ group, where R′ is asdefined hereinabove.

A “thiocarboxy” group describes a —C(═S)—OR′ group, where R′ is asdefined herein.

A “sulfinyl” group describes an —S(═O)—R′ group, where R′ is as definedherein.

A “sulfonyl” or “sulfonate” group describes an —S(═O)₂—R′ group, whereRx is as defined herein.

A “carbamyl” or “carbamate” group describes an —OC(═O)—NR′R″ group,where R′ is as defined herein and R″ is as defined for R′.

A “nitro” group refers to a —NO₂ group.

A “cyano” or “nitrile” group refers to a —C≡N group.

As used herein, the term “azide” refers to a —N₃ group.

The term “sulfonamide” refers to a —S(═O)₂—NR′R″ group, with R′ and R″as defined herein.

The term “phosphonyl” or “phosphonate” describes an —O—P(═O)(OR′)₂group, with R′ as defined hereinabove.

The term “phosphinyl” describes a —PR′R″ group, with R′ and R″ asdefined hereinabove.

The term “alkaryl” describes an alkyl, as defined herein, whichsubstituted by an aryl, as described herein. An exemplary alkaryl isbenzyl.

The term “heteroaryl” describes a monocyclic or fused ring (i.e., ringswhich share an adjacent pair of atoms) group having in the ring(s) oneor more atoms, such as, for example, nitrogen, oxygen and sulfur and, inaddition, having a completely conjugated pi-electron system. Examples,without limitation, of heteroaryl groups include pyrrole, furane,thiophene, imidazole, oxazole, thiazole, pyrazole, pyridine, pyrimidine,quinoline, isoquinoline and purine. The heteroaryl group may besubstituted or unsubstituted by one or more substituents, as describedhereinabove. Representative examples are thiadiazole, pyridine, pyrrole,oxazole, indole, purine and the like.

As used herein, the terms “halo” and “halide”, which are referred toherein interchangeably, describe an atom of a halogen, that is fluorine,chlorine, bromine or iodine, also referred to herein as fluoride,chloride, bromide and iodide.

The term “haloalkyl” describes an alkyl group as defined above, furthersubstituted by one or more halide(s).

Pharmaceutical Composition:

According to an aspect of embodiments of the invention there is provideda pharmaceutical composition comprising one or more compounds producedby the process disclosed herein, and a pharmaceutically acceptablecarrier.

Exemplary compounds include drugs and natural products known in the art,having attached with alkyl substituents, including, for example andwithout limitation, Ibuprofen, Beclorbrate, Captodiamine, andMontelukast:

According to some embodiments of the invention, the composition is beingpackaged in a packaging material and identified in print, in or on thepackaging material, for use in the treatment of a medical conditionassociated with any disease, medical condition, or disorder.

According to an aspect of embodiments of the invention there is provideda use of any one of the compound described herein as a medicament.

According to an aspect of embodiments of the invention there is provideda use of any one of the compound described herein in the manufacture ofa medicament for treating a medical condition associated with a disease,medical condition, or disorder.

The compounds described hereinabove may be administered or otherwiseutilized in this and other aspects of the present invention, either asis, or as a pharmaceutically acceptable salt, enantiomer, diastereomer,solvate, hydrate or a prodrug thereof.

The phrase “pharmaceutically acceptable salt” refers to a chargedspecies of the parent compound and its counter ion, which is typicallyused to modify the solubility characteristics of the parent compoundand/or to reduce any significant irritation to an organism by the parentcompound, while not abrogating the biological activity and properties ofthe administered compound. The neutral forms of the compounds may beregenerated by contacting the salt with a base or acid and isolating theparent compound in a conventional manner. The parent form of thecompound differs from the various salt forms in certain physicalproperties, such as solubility in polar solvents, but otherwise thesalts are equivalent to the parent form of the compound for the purposesof the present invention. The phrase “pharmaceutically acceptable salts”is meant to encompass salts of the active compounds that are preparedwith relatively nontoxic acids or bases, depending on the particularsubstituents found on the compounds described herein.

Non-limiting examples of pharmaceutically acceptable acid addition saltsinclude those derived from inorganic acids like hydrochloric,hydrobromic, nitric, carbonic, monohydrogencarbonic, phosphoric,monohydrogenphosphoric, dihydrogenphosphoric, sulfuric,monohydrogensulfuric, hydriodic, or phosphorous acids and the like, aswell as the salts derived from relatively nontoxic organic acids likeacetic, propionic, isobutyric, maleic, malonic, benzoic, succinic,suberic, fumaric, lactic, mandelic, phthalic, benzenesulfonic,p-tolylsulfonic, citric, tartaric, methanesulfonic, and the like. Alsoincluded are salts of amino acids such as arginate and the like, andsalts of organic acids like glucuronic or galactunoric acids and thelike (see, for example, Berge et al., “Pharmaceutical Salts”, Journal ofPharmaceutical Science, 1977, 66, 1-19). Certain specific compounds ofthe present invention contain both basic and acidic functionalities thatallow one or more compounds described herein to be converted into eitherbase or acid addition salts.

The neutral forms of the compounds as described herein are preferablyregenerated by contacting the salt with a base or acid and isolating theparent compounds in a conventional manner.

The term “prodrug” refers to an agent, which is converted into theactive compound (the active parent drug) in vivo. Prodrugs are typicallyuseful for facilitating the administration of the parent drug. Theprodrug may also have improved solubility as compared with the parentdrug in pharmaceutical compositions. Prodrugs are also often used toachieve a sustained release of the active compound in vivo.

The compounds described herein may possess asymmetric carbon atoms(optical centers) or double bonds; the racemates, diastereomers,geometric isomers and individual isomers are encompassed within thescope of the present invention.

As used herein, the term “enantiomer” describes a stereoisomer of acompound that is superposable with respect to its counterpart only by acomplete inversion/reflection (mirror image) of each other. Enantiomersare said to have “handedness” since they refer to each other like theright and left hand. Enantiomers have identical chemical and physicalproperties except when present in an environment which by itself hashandedness, such as all living systems.

The compounds described herein can exist in unsolvated forms as well assolvated forms, including hydrated forms. In general, the solvated formsare equivalent to unsolvated forms and are encompassed within the scopeof the present invention. Certain compounds of the present invention mayexist in multiple crystalline or amorphous forms. In general, allphysical forms are equivalent for the uses contemplated by the presentinvention and are intended to be within the scope of the presentinvention.

The term “solvate” refers to a complex of variable stoichiometry (e.g.,di-, tri-, tetra-, penta-, hexa-, and so on), which is formed by asolute (the conjugate described herein) and a solvent, whereby thesolvent does not interfere with the biological activity of the solute.Non-limiting exemplary suitable solvents include, for example, ethanol,acetic acid and the like.

The term “hydrate” refers to a solvate, as defined hereinabove, wherethe solvent is water.

According to another aspect of embodiments of the invention there isprovided a pharmaceutical composition comprising, as an activeingredient, any of the compounds described herein produced by thedisclosed process and a pharmaceutically acceptable carrier.

Accordingly, in any of the methods and uses described herein, any of thecompounds described herein can be provided to an individual either perse, or as part of a pharmaceutical composition where it is mixed with apharmaceutically acceptable carrier.

As used herein a “pharmaceutical composition” refers to a preparation ofone or more of the compounds described herein (as active ingredient), orphysiologically acceptable salts or prodrugs thereof, with otherchemical components including, but not limited to, physiologicallysuitable carriers, excipients, lubricants, buffering agents,antimicrobial agents, bulking agents (e.g. mannitol), antioxidants(e.g., ascorbic acid or sodium bisulfite), anti-inflammatory agents,anti-viral agents, chemotherapeutic agents, anti-histamines and thelike. The purpose of a pharmaceutical composition is to facilitateadministration of a compound to a subject. The term “active ingredient”refers to a compound, which is accountable for a biological effect.

The terms “physiologically acceptable carrier” and “pharmaceuticallyacceptable carrier”, which may be interchangeably used, refer to acarrier or a diluent that does not cause significant irritation to anorganism and does not abrogate the biological activity and properties ofthe administered compound.

Herein the term “excipient” refers to an inert substance added to apharmaceutical composition to further facilitate administration of adrug. Examples, without limitation, of excipients include calciumcarbonate, calcium phosphate, various sugars and types of starch,cellulose derivatives, gelatin, vegetable oils and polyethylene glycols.

Techniques for formulation and administration of drugs may be found in“Remington's Pharmaceutical Sciences” Mack Publishing Co., Easton, Pa.,latest edition, which is incorporated herein by reference.

Pharmaceutical compositions for use in accordance with the presentinvention thus may be formulated in conventional manner using one ormore pharmaceutically acceptable carriers comprising excipients andauxiliaries, which facilitate processing of the compounds intopreparations which can be used pharmaceutically. Proper formulation isdependent upon the route of administration chosen. The dosage may varydepending upon the dosage form employed and the route of administrationutilized. The exact formulation, route of administration and dosage canbe chosen by the individual physician in view of the patient's condition(see e.g., Fingl et al., 1975, in “The Pharmacological Basis ofTherapeutics”, Ch. 1 p. 1).

The pharmaceutical composition may be formulated for administration ineither one or more of routes depending on whether local or systemictreatment or administration is of choice, and on the area to be treated.Administration may be done orally, by inhalation, or parenterally, forexample by intravenous drip or intraperitoneal, subcutaneous,intramuscular or intravenous injection, or topically (includingophtalmically, vaginally, rectally, intranasally).

Formulations for topical administration may include but are not limitedto lotions, ointments, gels, creams, suppositories, drops, liquids,sprays and powders. Conventional pharmaceutical carriers, aqueous,powder or oily bases, thickeners and the like may be necessary ordesirable.

Compositions for oral administration include powders or granules,suspensions or solutions in water or non-aqueous media, sachets, pills,caplets, capsules or tablets. Thickeners, diluents, flavorings,dispersing aids, emulsifiers or binders may be desirable.

Formulations for parenteral administration may include, but are notlimited to, sterile solutions that may also contain buffers, diluentsand other suitable additives. Slow release compositions are envisagedfor treatment.

The amount of a composition to be administered will, of course, bedependent on the subject being treated, the severity of the affliction,the manner of administration, the judgment of the prescribing physician,etc.

The pharmaceutical composition may further comprise additionalpharmaceutically active or inactive agents such as, but not limited to,an antibacterial agent, an antioxidant, a buffering agent, a bulkingagent, a surfactant, an anti-inflammatory agent, an anti-viral agent, achemotherapeutic agent and an anti-histamine.

Compositions of the present invention may, if desired, be presented in apack or dispenser device, such as an FDA approved kit, which may containone or more unit dosage forms containing the active ingredient. The packmay, for example, comprise metal or plastic foil, such as a blisterpack. The pack or dispenser device may be accompanied by instructionsfor administration. The pack or dispenser may also be accommodated by anotice associated with the container in a form prescribed by agovernmental agency regulating the manufacture, use or sale ofpharmaceuticals, which notice is reflective of approval by the agency ofthe form of the compositions or human or veterinary administration. Suchnotice, for example, may be of labeling approved by the U.S. Food andDrug Administration for prescription drugs or of an approved productinsert.

Agrochemical Composition:

According to an aspect of embodiments of the invention there is providedan agrochemical composition comprising one or more compounds asdescribed herein.

Herein, with respect to the field and art of the present invention, an‘agrochemical’ is to be understood as generally being any chemical,biological, or/and physical, entity, structure, substance, material,compound, composition, formulation, or organism, singly or incombination, which is applied or dispensed to, or/and upon, the outer(air or atmosphere exposed) surface of an agricultural substrate (asdefined hereinabove) or/and immediately surrounding environment of anagricultural substrate, as part of cultivating, breeding, raising,growing, developing, maintaining, or/and storing, the agriculturalsubstrate.

A first main category of agrochemicals particularly relevant to thefield and art of the present invention includes agrochemicals thatpromote or/and enhance cultivating, breeding, raising, growing,developing, maintaining, or/and storing, of agricultural substrates, ina positive manner (i.e., with respect to the agricultural substrates).Exemplary sub-categories of agrochemicals included in this first maincategory of agrochemicals are fertilizers, growth stimulators, plantgrowth regulators (those which ‘positively’ promote or/and enhance plantgrowth and development), hormones, synergists, and similar types ofagrochemicals, which are applied or dispensed to, or/and upon, the outersurface or/and immediately surrounding environment of plant matter typesof an agricultural substrate, as part of cultivating, breeding, raising,growing, developing, maintaining, or/and storing, the plant matter, in apositive manner (i.e. with respect to the plant matter).

A second main category of agrochemicals particularly relevant to thedisclosed invention, in some embodiments thereof, includes agrochemicalsthat promote or/and enhance cultivating, breeding, raising, growing,developing, maintaining, or/and storing, of agricultural substrates, ina negative or inhibitory manner (i.e. against ‘enemies’ of theagricultural substrates). An exemplary sub-category of agrochemicals inthis second main category of agrochemicals is pesticides, which areapplied or dispensed to, or/and upon, the outer surface or/andimmediately surrounding environment of plant matter or animal mattertypes of an agricultural substrate, as part of cultivating, breeding,raising, growing, developing, or maintaining, the plant matter or animalmatter, in a negative or inhibitory manner (i.e., against enemy ‘pests’of the plant matter or animal matter).

A pesticide, as an important exemplary sub-category of agrochemicals, iscommonly known as generally being any chemical that is used to killpests, such as insects, and rodents. Herein, in a more encompassing andgeneral manner, which is particularly relevant to the disclosedcompounds, a pest may be considered as essentially any living plant oranimal organism, or any microorganism, which interferes with or/andinhibits cultivating, breeding, raising, growing, developing,maintaining, or/and storing, of agricultural substrates (plant matter,animal matter).

Pesticides may be divided and classified into major groups. Majorpesticide groups are: acaricides or miticides (lethal to ticks andmites), algicides, antifeedants, avicides (lethal to birds),bactericides, bird repellants, chemosterilants, fungicides, safeners,herbicides, insect attractants, insect repellants, insecticides, mammalrepellants, mating disrupters, molluscicides, nematicides, plantactivators (activate plant defense mechanisms against pests), plantgrowth regulators (those which inhibit pest plant growth), rodenticides,synergists, and virucides. This classified list of major pesticidesgroups represents at least fourteen hundred pesticide compounds.Moreover, each major pesticide group is sub-divided into chemical orother classes.

Catalyst Composition:

According to an aspect of embodiments of the invention there is provideda catalyst composition comprising: one or more Lewis acids selected fromthe group consisting of: CuCl₂, Sc(OTf)₃, Fe(OTf)₃, In(OTf)₃, BF₃.OEt₂,TfOH and Cu(OTf)₂; a polar solvent selected from the group consistingof: acetonitrile, nitromethane, and 2,2,2-trifluoroethanol (TFE), or amixture thereof, and RSH, wherein R is selected from the groupconsisting of: alkyl, benzyl, alkoxy, aryloxy, carbonyl, carboxy,substituted or non-substituted.

In some embodiments, the Lewis acid is in a molar concentration of atleast 1.

In some embodiments, the polar solvent is TFE.

It will be recognized that these embodiments are susceptible to variousmodifications and alternative forms well known to those of skill in theart.

The term “molar concentration” as used herein, may refer to aconcentration in units of mol/L at a temperature of approximately 25° C.

General:

As used herein the term “about” refers to ±10%.

The terms “comprises”, “comprising”, “includes”, “including”, “having”and their conjugates mean “including but not limited to”.

The term “consisting of” means “including and limited to”.

The term “consisting essentially of” means that the composition, methodor structure may include additional ingredients, steps and/or parts, butonly if the additional ingredients, steps and/or parts do not materiallyalter the basic and novel characteristics of the claimed composition,method or structure.

The word “exemplary” is used herein to mean “serving as an example,instance or illustration”. Any embodiment described as “exemplary” isnot necessarily to be construed as preferred or advantageous over otherembodiments and/or to exclude the incorporation of features from otherembodiments.

The word “optionally” is used herein to mean “is provided in someembodiments and not provided in other embodiments”. Any particularembodiment of the invention may include a plurality of “optional”features unless such features conflict.

As used herein, the singular form “a”, “an” and “the” include pluralreferences unless the context clearly dictates otherwise. For example,the term “a compound” or “at least one compound” may include a pluralityof compounds, including mixtures thereof.

Throughout this application, various embodiments of this invention maybe presented in a range format. It should be understood that thedescription in range format is merely for convenience and brevity andshould not be construed as an inflexible limitation on the scope of theinvention. Accordingly, the description of a range should be consideredto have specifically disclosed all the possible subranges as well asindividual numerical values within that range. For example, descriptionof a range such as from 1 to 6 should be considered to have specificallydisclosed subranges such as from 1 to 3, from 1 to 4, from 1 to 5, from2 to 4, from 2 to 6, from 3 to 6 etc., as well as individual numberswithin that range, for example, 1, 2, 3, 4, 5, and 6. This appliesregardless of the breadth of the range.

Whenever a numerical range is indicated herein, it is meant to includeany cited numeral (fractional or integral) within the indicated range.The phrases “ranging/ranges between” a first indicate number and asecond indicate number and “ranging/ranges from” a first indicate number“to” a second indicate number are used herein interchangeably and aremeant to include the first and second indicated numbers and all thefractional and integral numerals therebetween.

As used herein the terms “method” or “process”, which are usedhereinthroughout interchangeably, refer to manners, means, techniquesand procedures for accomplishing a given task including, but not limitedto, those manners, means, techniques and procedures either known to, orreadily developed from known manners, means, techniques and proceduresby practitioners of the chemical, pharmacological, biological,biochemical and medical arts.

As used herein, the term “treating” includes abrogating, substantiallyinhibiting, slowing or reversing the progression of a condition,substantially ameliorating clinical or aesthetical symptoms of acondition or substantially preventing the appearance of clinical oraesthetical symptoms of a condition.

It is appreciated that certain features of the invention, which are, forclarity, described in the context of separate embodiments, may also beprovided in combination in a single embodiment. Conversely, variousfeatures of the invention, which are, for brevity, described in thecontext of a single embodiment, may also be provided separately or inany suitable subcombination or as suitable in any other describedembodiment of the invention. Certain features described in the contextof various embodiments are not to be considered essential features ofthose embodiments, unless the embodiment is inoperative without thoseelements. The invention is capable of other embodiments or of beingpracticed or carried out in various ways.

It is appreciated that certain features of the invention, which are, forclarity, described in the context of separate embodiments, may also beprovided in combination in a single embodiment. Conversely, variousfeatures of the invention, which are, for brevity, described in thecontext of a single embodiment, may also be provided separately or inany suitable subcombination or as suitable in any other describedembodiment of the invention. Certain features described in the contextof various embodiments are not to be considered essential features ofthose embodiments, unless the embodiment is inoperative without thoseelements.

Various embodiments and aspects of the present invention as delineatedhereinabove and as claimed in the claims section below find support inthe following examples.

EXAMPLES

Reference is now made to the following examples, which together with theabove descriptions illustrate some embodiments of the invention in a nonlimiting fashion.

Materials and Methods:

All reagents were of reagent grade quality, purchased commercially fromSigma-Aldrich, Alfa-Aesar, or Fluka, and used without furtherpurification (Cu(OTf)₂ was purchased from stream chemicals. Purificationby column chromatography was performed on Merck chromatographic silicagel (40-60 μm). TLC analyses were performed using Merck silica gel glassplates 60 F254. NMR spectra were recorded on Bruker DPX400, or DMX500instruments; chemical shifts, given in, are relative to Me₄Si as theinternal standard or to the residual solvent peak. HR-MS data wereobtained using a Thermoscientific LTQU XL Orbitrap HRMS equipped withAPCI (atmospheric-pressure chemical ionization). Gas chromatography datawere obtained using an Agilent 7820A GC equipped with FID detectorworking under standard conditions and an Agilent HP-5 column. HPLCanalysis was carried out on an Agilent 1260 instrument equipped with aG4212-60008 photodiode array detector, ES-MS Advion Expression unit anda Agilent reverse phase ZORBAX Eclipse plus C18 3.5 μm column (4.6×100mm).

General Synthesis Route:

The synthesis route of the present invention is shown in scheme 1B (FIG.1B).

Without being bound by any particular theory or mechanism, it isproposed that the mechanism of the synthesis is as exemplified in scheme1 B (shown in FIG. 1B): in the first step (referred to as “Process A”hereinbelow) an aldehyde is reacted with ethyl thiol in the presence ofaffordable acid e.g., Lewis acids (such as: Cu(OTf)₂), to generatedi-thioacetal which is transformed to the active electrophilicspecies-thionium ion. When the arene is introduced it reacts to therebygenerate new carbon-carbon bond. In this process the alkyl scaffold isnot harmed and remains in its original structure.

Later the sulfide can be reduced with Et₃SiH as reducing agent in highlyselective manner (referred to as “Process B” hereinbelow).

FIG. 1A presents Scheme 1A showing a classic Friedel-Craft alkylation.

FIG. 1B presents, without being bound by any particular theory ormechanism, Scheme 1B showing the process of the present invention, insome embodiments thereof.

Example 1 Process A: Reaction of Aldehyde, Arene and Thiol

In exemplary procedures, the benzylation of electron rich arenes withbenzaldehydes of different electronic natures can be carried out in thepresence of different thiols.

Electron deficient aldehydes are more reactive than electron richaldehydes, while the reaction of benzaldehyde with 2,6-dimethylphenolusing thioacetic acid as the promoter reached completion within minutesat room temperature affording obtaining product A1 in 98% yields.

Polar functional groups, such as, —OH, —OMe, —CO₂H, —CN, —SMe, —Br and—NMe₂ are robust under the reaction conditions. The reaction is highlyefficient for both linear and branched aliphatic aldehydes, affordingbenzylsulfides such as A2:

in moderate to high yields (up to 92% yield).

Surprisingly, under the reaction conditions, side processes, such aspolyalkylation of the aromatic ring or nucleophilic substitution of thebenzylsulfide group were not observed. Similar to other electrophilicaromatic substitution reactions, this Pummerer/Friedel-Crafts reactionis reversible; the benzylsulfide products can decompose back to thedithioacetal and the arene coupling partners. This notion can explainthe high steric control that was observed in products that weresubstituted at the less hindered site.

Importantly, tertiary alkylchloride, which are highly reactive in theFriedel-Crafts reaction, are stable under the mild acidic conditions(product A3, 70%) of the reaction. The reaction of e.g.,1,3,5-trimethoxybenzene, with trimethyl orthoformate provided a directentry to masked aldehyde, A4 in 85%.

In additional exemplary procedures, the suitability of the method forthe synthesis of biologically active compounds was evaluated, as well,and the acid-sensitive 17β-estradiol with a secondary alcohol group (A570% yield),

the N-Ts protected indole (A6, 98%) and the N-Cbz-protected tyrosine (A7and A8 in 98% and 41% respectively) were successfully alkylated.

Synthesis of Specific Compounds:

In exemplary procedures of process A (also referred to herein as “methodA”), a solution of aldehyde (0.75 mmol), arene (0.25 mmol), ethanethiol(1.5 mmol) and Cu(OTf)₂ (2.5 mol %) in 2,2,2-trifluoroethanol (0.75 mL),(1.5 mmol) was stirred at the required temperature. Upon completion, allvolatiles were removed under reduced pressure and the crude residuepurified over silica-gel chromatography affording the desired couplingproduct.

Compound 3:

4-Anisaldehyde (91 μl, 0.75 mmol), Cu(OTf)₂ (2.2 mg, 2.5 mol %),ethanethiol (108 μl, 1 mmol) and anisole (27 μl, 0.25 mmol) were reactedaccording to method A. The mixture was stirred for 7 h at 50° C. Theresidual material was purified by column chromatography (silica gel40-60, hexane/ethyl acetate 98:2) affording compound 3 (39 mg, 54%yield) as a white solid. Characterization data of compound 3: ¹H NMR(CDCl₃/400 MHz): δ 7.34 (d, J=8.6 Hz, 4H), 6.85 (d, J=8.6 Hz, 2H), 5.13(s, 1H), 3.79 (s, 6H), 2.39 (q, J=7.4 Hz, 2H), 1.22 (t, J=7.4 Hz, 3H);¹³C NMR (CDCl₃/100 MHz): δ 158.6, 133.9, 129.3, 113.9, 55.3, 52.4, 26.2,14.3; HRMS (ESI): m/z calcd for C₁₇H₂₀O₂S [M+Na]⁺ 311.1076, found311.1075.

Compound 4:

3-Bromobenzaldehyde (92.5 mg, 0.5 mmol), Cu(OTf)₂ (2.2 mg, 2.5 mol %),ethanethiol (72 μl, 1 mmol) and anisole (27 μl, 0.25 mmol) were reactedaccording to method A. The mixture was stirred for 7 h at 50° C. Theresidual material was purified by column chromatography (silica gel40-60, hexane/ethyl acetate 97:3) affording compound 4 (59 mg, 70%yield) as white solid. Characterization data of compound 4: ¹H NMR(CDCl₃/400 MHz): δ 7.56 (s, 1H), 7.35 (d, J=8.2 Hz, 2H), 7.30 (d, J=8.6Hz, 2H), 7.17 (t, J=7.8 Hz, 1H), 6.85 (d, J=8.6 Hz, 2H), 5.09 (s, 1H),3.79 (s, 3H), 2.39 (q, J=7.4 Hz, 2H), 1.21 (t, J=7.4 Hz, 3H); ¹³C NMR(CDCl₃/100 MHz): δ 158.8, 144.3, 132.8, 131.3, 130.2, 130.1, 129.3,126.9, 122.6, 114.0, 55.3, 52.6, 26.3, 14.2; HRMS (ESI): m/z calcd forC₁₆H₁₇BrOS [M+Na]⁺ 359.0076 and 361.0055, found 359.0077 and 361.0050.

Compound 5:

4-Cyanobenzaldehyde (98 mg, 0.75 mmol), Cu(OTf)₂ (2.2 mg, 2.5 mol %),ethanethiol (108 μl, 1.5 mmol) and anisole (27 μl, 0.25 mmol) werereacted according to method A. The mixture was stirred for 16 h at 50°C. The residual material was purified by column chromatography (silicagel 40-60, hexane/ethyl acetate 93:7) affording compound 5 (64 mg, 90%yield) as a white solid. Characterization data of compound 5: ¹H NMR(CDCl₃/400 MHz): δ 7.59 (d, J=8.2 Hz, 2H), 7.52 (d, J=8.1 Hz, 2H), 7.29(d, J=8.7 Hz, 2H), 6.86 (d, J=8.9 Hz, 2H), 5.15 (s, 1H), 3.78 (s, 3H),2.39 (q, J=7.4 Hz, 2H), 1.21 (t, J 7.4 Hz, 3H); ¹³C NMR (CDCl₃/100 MHz):δ 159.0, 147.5, 132.4, 132.1, 129.3, 129.0, 118.8, 114.2, 110.8, 55.3,52.9, 26.3, 14.2; HRMS (ESI): m/z calcd for C₁₇H₁₇NO₃[M+Na]⁺ 306.1101,found 306.0925.

Compound 6:

Benzaldehyde (77 μl, 0.75 mmol), Cu(OTf)₂ (2.2 mg, 2.5 mol %),ethanethiol (108 μl, 1.5 mmol) and 1,3,5-trimethoxybenzene (42 mg, 0.25mmol) were reacted according to method A. The mixture was stirred for 4h at 50° C. The residual material was purified by column chromatography(silica gel 40-60, hexane/ethyl acetate 96:4) affording compound 6 (74mg, 94% yield) as a thick liquid. Characterization data of compound 6:¹H NMR (CDCl₃/400 MHz): δ 7.52 (d, J=7.7 Hz, 2H), 7.25 (t, J=7.7 Hz,2H), 7.15 (t, J=7.3 Hz, 1H), 6.13 (s, 2H), 5.70 (s, 1H), 3.79 (s, 3H),3.76 (s, 6H), 2.65-2.52 (m, 2H), 1.28 (t, J=7.3 Hz, 3H); ¹³C NMR(CDCl₃/100 MHz): δ 160.3, 158.5, 142.9, 128.0, 127.6, 125.9, 112.8,91.4, 55.9, 55.3, 43.3, 27.4, 14.8; HRMS (ESI): m/z calcd for C₁₈H₂₂O₃S[M+Na]⁺ 341.1182, found 341.1182.

Compound 7:

Benzaldehyde (77 μl, 0.75 mmol), Cu(OTf)₂ (2.2 mg, 2.5 mol %), isopropylthiol (140 μl, 1.5 mmol) and 1,3,5-trimethoxybenzene (42 mg, 0.25 mmol)were reacted according to method A. The mixture was stirred for 6.5 h at50° C. The residual material was purified by column chromatography(silica gel 40-60, hexane/ethyl acetate 94:6) affording compound 7 (77mg, 92% yield) as colorless crystals. Characterization data of compound7: ¹H NMR (CDCl₃/400 MHz): δ 7.60-7.55 (m, 2H), 7.25 (t, J=7.8 Hz, 2H),7.15 (t, J=7.1 Hz, 1H), 6.14 (s, 2H), 5.72 (s, 1H), 3.79 (s, 3H), 3.77(s, 6H), 3.02-2.91 (m, 2H), 1.31 (d, J=6.8, 3H), 1.30 (d, J=6.8, 3H);¹³C NMR (CDCl₃/100 MHz): δ 160.2, 158.2, 143.4, 128.2, 128.1, 128.0,127.7, 127.6, 126.0, 125.8, 113.5, 91.4, 55.9, 55.3, 42.3, 36.6, 23.7,14.7; HRMS (ESI): m/z calcd for C₁₉H₂₄O₃S [M+Na]⁺ 355.1338, found355.1338.

Compound 8:

Benzaldehyde (77 μl, 0.75 mmol), Cu(OTf)₂ (2.2 mg, 2.5 mol %), benzylthiol (176 μl, 1.5 mmol) and 1,3,5-trimethoxybenzene (42 mg, 0.25 mmol)were reacted according to method A. The mixture was stirred for 5 h at50° C. The residual material was purified by column chromatography(silica gel 40-60, hexane/ethyl acetate 94:6) affording compound 8 (62mg, 65% yield) as pale yellow crystals. Characterization data ofcompound 8: ¹H NMR (CDCl₃/400 MHz): δ 7.52-7.51 (m, 2H), 7.35-7.21 (m,8H), 7.19-7.15 (m, 1H), 6.11 (s, 2H), 5.64 (s, 1H), 3.79 (s, 3H), 3.75(d, J=2.6 Hz, 2H), 3.70 (s, 6H); ¹³C NMR (CDCl₃/100 MHz): δ 160.3,158.6, 142.3, 138.9, 129.2, 128.3, 128.1, 127.7, 126.7, 126.0, 112.2,91.2, 55.8, 55.3, 42.9, 37.6; HRMS (ESI): m/z calcd for C₂₃H₂₄O₃S[M+Na]⁺ 403.1338, found 403.1337.

Compound 9:

Benzaldehyde (51 mg, 0.5 mmol), Cu(OTf)₂ (2.2 mg, 2.5 mol %),2-phenylpropane-1-thiol (152 mg, 1 mmol) and 3,4,5-trimethoxyphenol (46mg, 0.25 mmol) were reacted according to method A. The mixture wasstirred for 8 h at 50° C. The residual material was purified by columnchromatography (silica gel 40-60, hexane/ethyl acetate 93:7) to obtaincompound 9 (87 mg, 82% yield) as a thick oil. Characterization data ofcompound 9: ¹H NMR (CDCl₃/400 MHz): δ 8.19 (s, 1H), 7.37-7.15 (m, 10H),6.36 (s, 1H), 5.86 (s, 1H), 3.85 (s, 3H), 3.82 (s, 3H), 3.68 (s, 3H),3.06-2.94 (m, 2H), 2.56 (dd, J=13.3, 9.0 Hz, 2H), 14.1 (d, J=6.9 Hz,3H); ¹³C NMR (CDCl₃/100 MHz): δ 153.8, 153.1, 152.4, 145.3, 144.9,139.2, 139.2, 135.8, 128.6, 128.5, 128.1, 128.0, 127.5, 127.0, 126.7,126.6, 109.1, 108.8, 97.8, 61.5, 61.0, 55.8, 45.1, 44.3, 40.6, 39.5,39.0, 21.4, 20.3; HRMS (ESI): m/z calcd for C₂₅H₂₈O₄S [M+Na]⁺ 447.1601,447.1593 found 389.1316, 391.1322.

Compound 10:

Benzaldehyde (77 μl, 0.75 mmol), Cu(OTf)₂ (2.2 mg, 2.5 mol %),thioacetic acid (107 μl, 1.5 mmol) and 2,6-dimethylphenol (30.5 mg, 0.25mmol) were reacted according to method A. The mixture was stirred for 20min at room temperature. The residual material was purified by columnchromatography (silica gel 40-60, hexane/ethyl acetate 95:5) affordingcompound 10 (70 mg, 98% yield) as a thick oil. Characterization data ofcompound 10: ¹H NMR (CDCl₃/400 MHz): δ 7.39-7.35 (m, 4H), 7.27-7.22 (m,1H), 6.97 (s, 2H), 5.88 (s, 1H), 2.36 (s, 3H), 2.21 (s, 6H); ¹³C NMR(CDCl₃/100 MHz): δ 194.5, 151.6, 141.5, 132.4, 128.6, 128.5, 128.2,127.2, 123.3, 51.5, 30.4, 16.1; HRMS (ESI): m/z calcd for C₁₇H₁₈O₂S[M+Na]⁺ 309.0920 found 309.0918.

Compound 11:

4-Hydroxybeznaldehyde (30.5 mg, 0.25 mmol), Cu(OTf)₂ (2.2 mg, 2.5 mol%), ethanethiol (54 μl, 0.75 mmol) and 1,3,5-trimethoxybenzne (54.6 mg,0.325 mmol) were reacted according to method A. The mixture was stirredfor 6 h at 50° C. The residual material was purified by columnchromatography (silica gel 40-60, hexane/ethyl acetate 65:35) affordingcompound 11 (75 mg, 89% yield) as a white solid. Characterization dataof compound 11: ¹H NMR (CDCl₃/400 MHz): δ 7.36 (d, J=8.4 Hz, 2H), 6.68(d, J=8.8 Hz, 2H), 6.12 (s, 2H), 5.63 (s, 1H), 5.39 (br s, OH), 3.78 (s,3H), 3.75 (s, 6H), 2.61-2.49 (m, 2H), 1.25 (t, J=7.4 Hz, 3H); ¹³C NMR(CDCl₃/100 MHz): δ 160.1, 158.4, 153.8, 134.9, 129.2, 114.6, 112.8,91.5, 55.9, 55.4, 42.7, 27.3, 14.7; HRMS (ESI): m/z calcd for C₁₈H₂₂O₄S[M+Na]⁺ 357.1131, found 357.1129.

Compound 12:

4-Carboxybeznaldehyde (112.5 mg, 0.75 mmol), Cu(OTf)₂ (2.2 mg, 2.5 mol%), ethanethiol (108 μl, 1.5 mmol) and 1,3,5-trimethoxybenzne (42 mg,0.25 mmol) were reacted according to method A. The mixture was stirredfor 3 h at 50° C. The residual material was purified by columnchromatography (silica gel 40-60, hexane/ethyl acetate 60:40) affordingcompound 12 (54 mg, 60% yield) as a white solid. Characterization dataof compound 12: ¹H NMR (CDCl₃/400 MHz): δ 7.99 (d, J=8.5 Hz, 2H), 7.61(d, J=8.1 Hz, 2H), 6.10 (s, 2H), 5.70 (s, 1H), 3.79 (s, 3H), 3.74 (s,6H), 2.64-2.51 (m, 2H), 1.27 (t, J=7.4 Hz, 3H); ¹³C NMR (CDCl₃/100 MHz):δ 172.3, 160.6, 158.4, 149.6, 129.7, 128.1, 126.8, 111.9, 91.3, 55.8,55.3, 43.3, 27.4, 14.7; HRMS (ESI): m/z calcd for C₁₉H₂₂O₅S [M+Na]⁺385.1080, found 385.1080.

Compound 13:

3-Hydroxybenzaldehyde (91.5 mg, 0.75 mmol), Cu(OTf)₂ (2.2 mg, 2.5 mol%), ethanethiol (108 μl, 1.5 mmol) and 1,3,5-triethoxybenzene (52.5 mg,0.25 mmol). The mixture was stirred for 3 h at 50° C. The residualmaterial was purified by column chromatography (silica gel 40-60,hexane/ethyl acetate 95:5) affording compound 13 (77 mg, 82% yield) as athick oil. Characterization data of compound 13: ¹H NMR (CDCl₃/400 MHz):δ 7.08-7.07 (m, 3H), 6.62-6.60 (m, 1H), 6.08 (s, 2H), 5.66 (s, 1H), 4.96(br s, OH), 4.03-3.86 (m, 6H), 2.63-2.50 (m, 2H), 1.39 (t, J=7.0 Hz,3H), 1.31 (t, J=6.9 Hz, 6H), 1.28 (t, J=7.3 Hz, 3H); ¹³C NMR (CDCl₃/100MHz): δ 159.4, 157.6, 155.0, 145.2, 128.6, 120.6, 115.2, 112.8, 112.6,92.3, 64.1, 63.5, 42.9, 27.2, 14.9, 14.86, 14.8; HRMS (ESI): m/z calcdfor C₂₁H₂₈O₄S [M+Na]⁺ 399.1601, found 399.1588.

Compound 14:

4-Cyanobenzaldehyde (98 mg, 0.75 mmol), Cu(OTf)₂ (27 mg, 30 mol %),ethanethiol (108 μl, 1.5 mmol) and mesitylene (35 μl, 0.25 mmol) werereacted according to method A. The mixture was stirred for 16 h at 70°C. The residual material was purified by column chromatography (silicagel 40-60, hexane/diethylether 95:5) affording compound 14 (64 mg, 87%yield) as a white solid. Characterization data of compound 14: ¹H NMR(CDCl₃/400 MHz): δ 7.58-7.56 (m, 2H), 7.53-7.51 (m, 2H), 6.85 (s, 2H),5.58 (s, 1H), 2.72-2.52 (m, 2H), 2.67 (s, 3H), 2.18 (br s, 6H), 1.30 (t,J=7.4 Hz, 3H); ¹³C NMR (CDCl₃/100 MHz): δ 147.2, 137.1, 136.6, 135.2,132.0, 130.4 (br s), 128.6, 126.6, 119.0, 110.1, 48.2, 27.2, 21.1, 20.9,203, 14.8; HRMS (ESI): m/z calcd for C₁₉H₂₁NS [M+Na]⁺ 318.1287, found318.1285.

Compound 15:

4-Cyanobenzaldehyde (98 mg, 0.75 mmol), Cu(OTf)₂ (27 mg, 30 mol %),ethanethiol (108 μl, 1.5 mmol) and thioanisole (38.5 mg, 0.25 mmol) werereacted according to method A. The mixture was stirred for 16 h at 90°C. in sealed tube. The residual material was purified by columnchromatography (silica gel 40-60, hexane/diethylether 90:10) affordingcompound 15 (60 mg, 80% yield) as a white solid. Characterization dataof compound 15: ¹H NMR (CDCl₃/400 MHz): δ 7.59 (d, J=8.3 Hz, 2H), 7.51(d, J=8.3 Hz, 2H), 7.29 (d, J=8.4 Hz, 2H), 7.20 (d, J=8.4 Hz, 2H), 5.15(s, 1H), 2.45 (s, 3H), 2.40 (q, J=7.4, 2H), 1.21 (t, J=7.4, 3H); ¹³C NMR(CDCl₃/100 MHz): δ 147.1, 138.1, 136.8, 132.4, 129.1, 128.7, 126.7,118.7, 111.0, 53.0, 26.4, 15.7, 14.2; HRMS (ESI): m/z calcd forC₁₇H₁₇NS₂ [M+Na]⁺ 322.0695, found 322.0699.

Compound 16:

Methyl 4-formylbenzoate (123 mg, 0.75 mmol), Cu(OTf)₂ (4.5 mg, 5 mol %),ethanethiol (108 μl, 1.5 mmol) and 1,4-dimethoxybenzene (38.5 mg, 0.25mmol) were reacted according to method A. The mixture was stirred for 7h at 70° C. in sealed tube. The residual material was purified by columnchromatography (silica gel 40-60, hexane/ethyl acetate 95:5) affordingcompound 16 (32 mg, 36% yield) as a white solid. Characterization dataof compound 16: ¹H NMR (CDCl₃/400 MHz): δ 7.95 (d, J=7.9 Hz, 2H), 7.50(d, J=7.9 Hz, 2H), 7.19 (s, 1H), 6.80-6.71 (m, 2H), 5.67 (s, 1H), 3.88(s, 3H), 3.76 (s, 3H), 3.74 (s, 3H), 2.43 (q, J=7.3, 2H), 1.22 (t,J=7.3, 3H); ¹³C NMR (CDCl₃/100 MHz): δ 167.0, 153.8, 150.9, 147.1,130.4, 129.7, 128.6, 128.4, 115.2, 112.6, 111.9, 56.3, 55.7, 52.0, 45.9,26.4, 14.3; HRMS (ESI): m/z calcd for C₁₉H₂₂O₄S [M+Na]⁺ 369.1131, found369.1128.

Compound 18:

Benzaldehyde (77 μl, 0.75 mmol), Cu(OTf)₂ (27 mg, 30 mol %), ethanethiol(108 μl, 1.5 mmol) and protected tyrosine (85.7 mg, 0.25 mmol) werereacted according to method A. The mixture was stirred for 10 h at 70°C. The residual material was purified by column chromatography (silicagel 40-60, hexane/ethyl acetate 70:30) affording compound 18 (51 mg, 41%yield) as a thick oil. Characterization data of compound 18: ¹H NMR(CDCl₃/400 MHz): δ 7.37-7.22 (m, 10H), 6.93 (dt, J=8.1, 2.5 Hz, 1H),6.84-6.78 (m, 2H), 5.31 (d, J=7.1 Hz, 1H), 5.22-5.16 (m, 1H), 5.07 (d,J=4.1 Hz, 2H), 4.59-4.52 (m, 1H), 4.11-3.92 (m, 2H), 3.04-2.94 (m, 2H),2.43 (q, J=7.2 Hz, 2H), 1.22 (t, J=7.3 Hz, 3H), 1.16 (t, J=6.9 Hz, 3H);¹³C NMR (CDCl₃/100 MHz): δ 171.5, 155.6, 154.3, 139.1, 136.3, 133.6,131.0, 130.8, 128.7, 128.6, 128.4, 128.3, 128.2, 128.1, 127.5, 125.2,117.7, 67.0, 61.5, 61.4, 54.8, 50.3, 37.5, 26.3, 14.1; HRMS (ESI): m/zcalcd for C₂₈H₃₁NO₅S [M+Na]⁺ 516.1815 found 516.1943.

Compound 19:

Methyl 4-formylbenzoate (123 mg, 0.75 mmol), Cu(OTf)₂ (18 mg, 20 mol %),ethanethiol (108 μl, 1.5 mmol) and protected tyrosine (85.7 mg, 0.25mmol) were reacted according to method A. The mixture was stirred for 11h at 70° C. The residual material was purified by column chromatography(silica gel 40-60, hexane/ethyl acetate 70:30) affording compound 19 (51mg, 37% yield) as a thick oil. Characterization data of compound 19: ¹HNMR (CDCl₃/400 MHz): δ 7.95 (dd, J=4.3, 4.0 Hz, 2H), 7.45 (dd, J=8.0,2.5 Hz, 2H), 7.35-7.30 (m, 5H), 6.96-6.88 (m, 3H), 6.76-6.68 (m, 1H),5.43 (s, 1H), 5.25 (d, J=7.1 Hz, 1H), 5.07 (s, 2H), 4.60-4.54 (m, 1H),4.17-4.00 (m, 2H), 3.88 (s, 3H), 3.04-2.95 (m, 2H), 2.45-2.39 (m, 2H),1.27-1.16 (m, 6H), 2.16-2.07 (m, 1H), 1.01 (d, J=6.6 Hz, 3H), 0.75 (d,J=6.7 Hz, 3H); ¹³C NMR (CDCl₃/100 MHz): δ 159.7, 158.9, 139.5, 113.7,113.4, 91.2, 90.7, 56.1, 55.1, 42.4, 35.7, 30.8, 21.9; HRMS (ESI): m/zcalcd for C₃₀H₃₃NO₇S [M+Na]⁺ 574.1870 found 574.1861.

Compound 20:

Benzaldehyde (77 μl, 0.75 mmol), Cu(OTf)₂ (2.2 mg, 2.5 mol %),ethanethiol (108 μl, 1.5 mmol) and 1H-Indole,1-[(4-methylphenyl)sulfonyl]-(67.25 mg, 0.25 mmol) were reactedaccording to method A. The mixture was stirred for 4 h at 50° C. Theresidual material was purified by column chromatography (silica gel40-60, hexane/ethyl acetate 93:7) affording compound 20 (104 mg, 98%yield) as a thick yellowish oil. Characterization data of compound 20:¹H NMR (CDCl₃/400 MHz): δ 8.00 (d, J=8.2 Hz, 1H), 7.78 (d, J=7.9 Hz,2H), 7.60 (s, 1H), 7.49 (d, J=7.9 Hz, 1H), 7.42 (d, J=8.2 Hz, 2H),7.35-7.26 (m, 4H), 7.24 (d, J=8.4 Hz, 2H), 7.19 (t, J=7.6 Hz, 1H), 5.31(s, 1H), 2.50-2.43 (m, 2H), 2.37 (s, 3H), 1.25 (t, J=7.4 Hz, 3H); ¹³CNMR (CDCl₃/100 MHz): δ 145.0, 140.2, 135.7, 135.1, 129.9, 129.7, 128.6,128.2, 127.5, 126.9, 126.8, 125.0, 124.9, 123.4, 123.2, 120.5, 113.9,45.2, 26.2, 21.6, 14.4; HRMS (ESI): m/z calcd for C₂₄H₂₃NO₂S₂ [M+Na]⁺444.1062 found 444.1067.

Compound 21:

Isobutyrlaldehyde (68.4 μl, 0.75 mmol), Cu(OTf)₂ (2.2 mg, 2.5 mol %),ethanethiol (108 μl, 1.5 mmol) and 2-naphthol (36 mg, 0.25 mmol) werereacted according to method A. The mixture was stirred for 4 h at 50° C.The residual material was purified by column chromatography (silica gel40-60, hexane/diethylether 98:2) affording compound 21 (57 mg, 87%yield) as a thick oil. Characterization data of compound 21: ¹H NMR(CDCl₃/400 MHz): δ 8.72 (s, OH), 7.93 (d, J=8.7 Hz, 1H), 7.78 (d, J=8.0Hz, 1H), 7.72 (d, J=8.9 Hz, 1H), 7.47 (ddd, J=1.4, 6.8, 9.0 Hz, 1H),7.33 (ddd, J=0.9, 6.7, 8.8 Hz, 1H), 7.15 (d, J=8.8 Hz, 1H), 4.84 (d,J=8.7 Hz, 1H), 2.46-2.37 (m, 1H), 2.32-2.26 (m, 2H), 1.22 (t, J=6.6 Hz,3H), 1.12 (t, J=7.4 Hz, 3H), 0.84 (t, J=6.7 Hz, 3H); ¹³C NMR (CDCl₃/100MHz): δ 154.5, 134.0, 129.5, 129.1, 126.7, 122.9, 122.0, 120.2, 116.0,49.7, 32.6, 25.0, 21.9, 21.3, 14.6; HRMS (ESI): m/z calcd for C₁₆H₂₀OS[M+Na]⁺ 283.1127, found 283.1066.

Compound 22:

Isobutyrlaldehyde (68.4 μl, 0.75 mmol), Cu(OTf)₂ (2.2 mg, 2.5 mol %),ethanethiol (108 μl, 1.5 mmol) and 6-bromo-2-naphthol (55.7 mg, 0.25mmol) were reacted according to method A. The mixture was stirred for 12h at 50° C. The residual material was purified by column chromatography(silica gel 40-60, hexane/diethylether 98:2) affording compound 22 (82mg, 97% yield) as a thick oil. Characterization data of compound 22: ¹HNMR

(CDCl₃/400 MHz): δ 8.70 (s, OH), 7.9 (d, J=2.2 Hz, 1H), 7.8 (d, J=9.3Hz, 1H), 7.6 (d, J=8.8 Hz, 1H), 7.5 (dd, J=2.2, 9 Hz, 1H), 7.15 (d,J=8.8 Hz, 1H), 4.73 (d, J=8.7 Hz, 1H), 2.41-2.3 (m, 1H), 2.26 (q, J=7.3Hz, 2H), 1.2 (t, J=6.5 Hz, 3H), 1.1 (t, J=7.4 Hz, 3H), 0.8 (t, J=6.7 Hz,3H); ¹³C NMR (CDCl₃/100 MHz): δ 154.7, 132.6, 130.9, 130.3, 129.8,128.6, 123.8, 121.3, 116.49, 116.41, 49.6, 32.5, 25.0, 21.9, 21.3, 14.6;HRMS (ESI): m/z calcd for C₁₆H₁₉BrOS [M+Na]⁺ 361.0232 and 363.0212,found 361.0242 and 363.0218.

Compound 23:

Isobutyrlaldehyde (68 μl, 0.75 mmol), Cu(OTf)₂ (2.2 mg, 2.5 mol %),ethanethiol (108 μl, 1.5 mmol) and trimethoxybenzene (42 mg, 0.25 mmol)were reacted according to method A. The mixture was stirred for 2 h at50° C. in sealed tube. The residual material was purified by columnchromatography (silica gel 40-60, hexane/ethyl acetate 96:4) affordingcompound 23 (60 mg, 85% yield) as a thick oil. Characterization data ofcompound 23: ¹H NMR (CDCl₃/400 MHz): δ 6.12 (s, 1H), 6.10 (s, 1H), 3.93(d, J=10.5 Hz, 1H), 3.80 (s, 3H), 3.79 (s, 3H), 3.77 (s, 3H), 2.50-2.35(m, 3H), 1.19 (d, J=6.7 Hz, 3H), 1.18 (t, J=7.8 Hz, 3H), 0.67 (d, J=6.7Hz, 3H); ¹³C NMR (CDCl₃/100 MHz): δ 159.6, 159.5, 157.8, 113.0, 91.7,90.3, 55.9, 55.7, 55.2, 47.8, 31.8, 27.3, 22.5, 21.4, 15.1; HRMS (ESI):m/z calcd for C₁₅H₂₄O₃S [M+Na]⁺ 307.1338, found 307.1337.

Compound 24:

Isobutyrlaldehyde (68.4 μl, 0.75 mmol), Cu(OTf)₂ (2.2 mg, 2.5 mol %),ethanethiol (108 μl, 1.5 mmol) and 3,4,5-trimethoxyphenol (46 mg, 0.25mmol) were reacted according to method A. The mixture was stirred for4.5 h at 50° C. The residual material was purified by columnchromatography (silica gel 40-60, hexane/ethyl acetate 95:5) affordingcompound 24 (62 mg, 82% yield) as a white solid. Characterization dataof compound 24: ¹H NMR (CDCl₃/400 MHz): δ 7.92 (s, OH), 6.22 (s. 1H),4.27 (d, J=9.2 Hz, 1H), 3.86 (s, 3H), 3.79 (s, 3H), 3.75 (s, 3H),2.37-2.23 (m, 2H), 2.16-2.07 (m, 1H), 1.14 (t, J=7.4 Hz, 3H), 1.10 (d,J=6.7 Hz, 3H), 0.81 (d, J=6.7 Hz, 3H); ¹³C NMR (CDCl₃/100 MHz): δ 153.0,152.5, 152.3, 135.3, 110.4, 97.3, 61.0, 60.8, 55.7, 48.2, 32.3, 25.1,21.7, 21.4, 14.3; HRMS (ESI): m/z calcd for C₁₅H₂₄O₄S [M+Na]⁺ 323.1288,found 323.1286.

Compound 25:

Isovaleraldehyde (68.4 μl), Cu(OTf)₂ (2.2 mg, 2.5 mol %), ethanethiol(108 μl, 1.5 mmol) and 3,4,5-trimethoxyphenol (46 mg). The mixture wasstirred for 4 h at 50° C. The residual material was purified by columnchromatography (silica gel 40-60, hexane/ethyl acetate 95:5) affordingcompound 25 (56 mg, 72% yield) as a thick oil. Characterization data ofcompound 25: ¹H NMR (CDCl₃/400 MHz): δ 7.85 (s, OH), 6.24 (s. 1H), 4.65(t, J=7.5 Hz, 1H), 3.86 (s, 3H), 3.79 (s, 3H), 3.76 (s, 3H), 2.40-2.25(m, 2H), 1.73-1.58 (m, 3H), 1.17 (t, J=7.4 Hz, 3H), 0.92 (d, J=7.3 Hz,3H), 0.89 (d, J=7.3 Hz, 3H); ¹³C NMR (CDCl₃/100 MHz): δ 153.0, 152.5,152.0, 135.4, 111.3, 97.6, 61.2, 60.9, 55.7, 43.1, 38.4, 26.2, 25.0,22.7, 22.1, 14.3; HRMS (ESI): m/z calcd for C₁₆H₂₆O₄S [M+Na]⁺ 337.1444,found 337.1441.

Compound 26:

Trimethylacetaldehyde (81 μl, 0.75 mmol), Cu(OTf)₂ (2.2 mg, 2.5 mol %),ethanethiol (108 μl, 1.5 mmol) and 3,5-dimethoxyphenol (38.5 mg, 0.25mmol) were reacted according to method A. The mixture was stirred for 16h at 70° C. The residual material was purified by column chromatography(silica gel 40-60, hexane/diethylether 97:3) affording compound 26 (66mg, 92% yield) as a white solid. Characterization data of compound 26:¹H NMR (CDCl₃/400 MHz): δ 8.79 (s, OH), 6.07 (d, J=2.4 Hz, 1H), 6.03 (d,J=2.5 Hz, 2H), 4.56 (s, 1H), 3.76 (s, 3H), 3.72 (s, 3H), 2.28 (q, J=7.6Hz, 2H), 1.14 (t, J=7.4 Hz, 3H), 1.01 (s, 9H); ¹³C NMR (CDCl₃/100 MHz):δ 160.1, 159.8, 158.6, 103.8, 94.8, 90.9, 55.5, 55.1, 50.5, 37.5, 28.5,24.9, 10.1; HRMS (ESI): m/z calcd for C₁₅H₂₄O₃S [M+Na]⁺ 307.1338, found307.1337.

Compound 27:

Acetaldehyde (42 μl, 0.75 mmol), Cu(OTf)₂ (2.2 mg, 2.5 mol %),ethanethiol (108 μl, 1.5 mmol) and sesamol (34.5 mg, 0.25 mmol) werereacted according to method A. The mixture was stirred for 1.5 h at 50°C. The residual material was purified by column chromatography (silicagel 40-60, hexane/diethylether 90:10) affording compound 27 (46 mg, 82%yield) as a thick oil. Characterization data of compound 27: ¹H NMR(CDCl₃/400 MHz): δ 7.13 (br s, OH), 6.57 (s, 1H), 6.45 (s, 1H), 5.88 (s,1H), 5.88 (s, 1H), 4.06 (q, J=7.1 Hz, 1H), 2.39 (q, J=7.3 Hz, 2H), 1.57(d, J=7.1 Hz, 3H), 1.19 (t, J=7.3 Hz, 3H); ¹³C NMR (CDCl₃/100 MHz): δ150.2, 147.5, 141.2, 118.7, 108.0, 101.1, 100.0, 41.7, 24.9, 20.4, 14.4;HRMS (ESI): m/z calcd for C₁₁H₁₄O₃S [M+Na]⁺ 249.0556, found 249.0547.

Compound 28:

Valeraldehyde (75 μl, 0.75 mmol), Cu(OTf)₂ (2.2 mg, 2.5 mol %),ethanethiol (108 μl, 1.5 mmol) and 2,6-dimethylphenol (30.5 mg, 0.25mmol) were reacted according to method A. The mixture was stirred for 3h at 50° C. The residual material was purified by column chromatography(silica gel 40-60, hexane/diethylether 93:7) affording compound 28 (47mg, 74% yield) as a colorless oil. Characterization data of compound 28:¹H NMR (CDCl₃/400 MHz): δ 6.90 (s, 2H), 3.66 (dd, J=8.6, 6.3 Hz, 1H),2.35-2.25 (m, 2H), 2.23 (s, 3H), 1.87-1.74 (m, 2H), 1.35-1.25 (m, 4H),1.16 (t, J=7.4 Hz, 3H), 0.86 (t, J=7.1 Hz, 3H); ¹³C NMR (CDCl₃/100 MHz):δ 160.0, 134.5, 127.9, 122.8, 48.9, 36.5, 30.0, 25.0, 22.5, 16.1, 14.5,14.0; HRMS (ESI): m/z calcd for C₁₅H₂₄OS [M+Na]⁺ 275.1440 found275.1434.

Compound 29:

Cyclopropanecarboxyaldehyde (56 μl, 0.75 mmol), Cu(OTf)₂ (2.2 mg, 2.5mol %), ethanethiol (108 μl, 1.5 mmol) and 3,5-dimethoxyphenol (38.5 mg,0.25 mmol) were reacted according to method A. The mixture was stirredfor 16 h at 8° C. The residual material was purified by columnchromatography (silica gel 40-60, hexane/ethyl acetate 97:3) affordingcompound 29 (19 mg, 28% yield) as a thick oil. Characterization data ofcompound 29: ¹H NMR (CDCl₃/500 MHz): δ 8.34 (s, OH), 6.12 (d, J=2.4 Hz,1H), 6.06 (d, J=2.4 Hz, 1H), 4.08 (d, J=9.7 Hz, 1H), 3.77 (s, 3H), 3.74(s, 3H), 2.36-2.25 (m, 2H), 1.31-1.24 (m, 1H), 1.13 (t, J=7.3 Hz, 3H),0.63-0.58 (m, 1H), 0.46-0.31 (m, 3H); ¹³C NMR (CDCl₃/125 MHz): δ 160.3,158.7, 158.1, 105.8, 94.9, 91.3, 55.7, 55.2, 43.9, 24.9, 14.8, 14.3,5.7, 5.2; HRMS (ESI): m/z calcd for C₁₄H₂₀O₃S [M+H]⁺ 269.1206, found269.1211.

Compound 30:

Trimethyl orthoformate (82 μl, 0.75 mmol), Cu(OTf)₂ (2.2 mg, 2.5 mol %),ethanethiol (108 μl, 1.5 mmol) and 1,3,5-trimethoxybenzene (42 mg, 0.25mmol) were reacted according to method A. The mixture was stirred for 6h at 50° C. The residual material was purified by column chromatography(silica gel 40-60, ethyl acetate/hexane 94:6) affording compound 30 (64mg, 85% yield) as a thick oil. Characterization data of compound 30: ¹HNMR (CDCl₃/500 MHz): δ 6.13 (s, 1H), 6.07 (s, 1H), 5.40 (s, 1H), 3.86(s, 3H), 3.79 (s, 3H), 3.78 (s, 3H), 2.60 (q, J=7.4 Hz, 4H), 1.24 (t,J=7.4 Hz, 6H); ¹³C NMR (CDCl₃/125 MHz): δ 160.5, 160.0, 156.3, 111.2,92.0, 90.3, 56.0, 55.9, 55.3, 43.4, 27.8, 14.7; HRMS (ESI): m/z calcdfor C₁₄H₂₂O₃S₂ [M+Na]⁺ 325.0903 found 325.0906.

Compound 31:

9-bromo-1-nonanal (165 mg, 0.75 mmol), Cu(OTf)₂ (2.2 mg, 2.5 mol %),ethanethiol (108 μl, 1.5 mmol) and 3,4,5-trimethoxyphenol (46 mg, 0.25mmol) were reacted according to method A. The mixture was stirred for 5h at 50° C. The residual material was purified by column chromatography(silica gel 40-60, hexane/ethyl acetate 92:8) affording compound 31 (87mg, 77% yield) as a thick oil. Characterization data of compound 31: ¹HNMR (CDCl₃/400 MHz): δ 7.86 (br s, OH), 6.24 (s, 1H), 4.55 (t, J=7.3 Hz,1H), 3.86 (s, 3H), 3.80 (s, 3H), 3.77 (s, 3H), 3.37 (t, J=6.8 Hz, 2H),2.41-2.26 (m, 2H), 1.85-1.77 (m, 4H), 1.41-1.20 (m, 10H), 1.17 (t, J=7.4Hz, 3H); ¹³C NMR (CDCl₃/100 MHz): δ 155.1, 152.4, 152.17, 135.4, 110.9,97.5, 61.2, 60.9, 55.7, 40.3, 34.0, 32.8, 29.2, 28.6, 28.1, 27.9, 25.1,14.3; HRMS (ESI): m/z calcd for C₂₀H₃₃BrO₄S [M+Na]+471.1175 and 473.115,found 471.1167 and 473.1149.

Compound 32:

7-chloro-3,7-dimethyloctanal (90 mg, 0.4 mmol), Cu(OTf)₂ (2.2 mg, 2.5mol %), ethanethiol (108 μl, 1.5 mmol) and 1,3,5-trimethoxybenzne (33.6mg, 0.2 mmol) were reacted according to method A. The mixture wasstirred for 0.5 h at 50° C. The residual material was purified by columnchromatography (silica gel 40-60, hexane/ethyl acetate 95:5) affordingcompound 32 (71 mg, 70% yield) as a thick oil. Characterization data ofcompound 32: ¹H NMR (CDCl₃/500 MHz): δ 6.12 (m, 1H), 6.10 (m, 1H),4.56-4.47 (m, 1H), 3.82 (s, 3H), 3.79 (s, 6H), 2.53-2.35 (m, 2H),1.98-1.83 (m, 1H), 1.67-1.58 (m, 2H), 1.53 (s, 3H), 1.52 (s, 3H),1.42-1.31 (m, 2H), 1.22-1.19 (m, 3H), 1.19-1.04 (m, 2H), 0.84 (t, J=5.5Hz, 3H); ¹³C NMR (CDCl₃/125 MHz): δ 160.2, 159.8, 158.2, 111.2, 91.7,90.3, 71.4, 55.9, 55.7, 55.3, 46.3, 41.2, 37.7, 37.1, 32.5, 31.5, 26.3,22.6, 19.5, 15.0; HRMS (ESI): m/z calcd for C₂₁H₃₄O₃S [M−(HCl)+Na]⁺389.2121 found 389.2124.

Compound 33:

7-hyroxycitronellal (140 μl, 0.75 mmol), Cu(OTf)₂ (2.2 mg, 2.5 mol %),ethanethiol (108 μl, 1.5 mmol) and 1,3,5-trimethoxybenzene (42 mg, 0.25mmol) were reacted according to method A. The mixture was stirred for 2h at room temperature. The residual material was purified by columnchromatography (silica gel 40-60, hexane/ethyl acetate 80:20) affordingcompound 33 (68 mg, 71% yield) as a thick oil. Characterization data ofcompound 33: ¹H NMR (CDCl₃/400 MHz): δ 6.12 (s, 1H), 6.09 (s, 1H),4.54-4.46 (m, 1H), 3.80 (s, 3H), 3.78 (s, 6H), 2.51-2.32 (m, 3H),1.96-1.84 (m, 1H), 1.56-1.47 (m, 1H), 1.40-1.32 (m, 4H), 1.24-1.19 (m,5H), 1.17 (s, 3H), 1.15 (s, 3H), 0.82 (t, J=4.5 Hz, 3H); ¹³C NMR(CDCl₃/100 MHz): δ 160.2, 159.8, 158.2, 112.4, 111.4, 91.7, 90.3, 71.0,55.9, 55.7, 55.2, 44.2, 41.3, 38.1, 37.1, 31.4, 29.1, 26.3, 21.6, 20.0,19.4, 15.0; HRMS (ESI): m/z calcd for C₂₁H₃₆O₄S [M+Na]⁺ 407.2227 found407.2218.

Compound 34:

Glutaraldehyde [25% V/V in H₂O] (188 μl, 0.75 mmol), Cu(OTf)₂ (9 mg, 10mol %), ethanethiol (108 μl, 1.5 mmol) and 1,3,5-trimethoxybenzene (42mg, 0.25 mmol) were reacted according to method A. The mixture wasstirred for 8 h at 50° C. The residual material was purified by columnchromatography (silica gel 40-60, hexane/ethyl acetate 95:5) affordingcompound 34 (61 mg, 58% yield) as a thick oil. Characterization data ofcompound 34: ¹H NMR (CDCl₃/400 MHz): δ 6.11 (s, 1H), 6.09 (s, 1H), 4.36(dd, J=9.2, 6.7 Hz, 1H), 3.80 (s, 3H), 3.78 (s, 6H), 3.69 (t, J=7.1 Hz,1H), 2.66-2.39 (m, 6H), 2.15-2.08 (m, 1H), 1.95-1.88 (m, 1H), 1.82-1.67(m, 2H), 1.54-1.47 (m, 1H), 1.45-1.38 (m, 1H), 1.21 (t, J=7.5 Hz, 3H),1.19 (t, J=7.5 Hz, 6H); ¹³C NMR (CDCl₃/100 MHz): δ 160.0, 159.8, 157.9,111.7, 91.7, 90.3, 55.9, 55.7, 55.3, 51.2, 39.0, 35.7, 33.9, 26.6, 26.2,24.1, 23.9, 15.1, 14.6, 14.5; HRMS (ESI): m/z calcd for C₂₀H₃₄O₃S₃[M+Na]⁺ 441.1562 found 441.1558.

Compound 35:

Compound 34 (40.8 mg, 0.1 mmol) was treated with Cu(OTf)₂ (0.8 mg, 2.5mol %) and Et₃SiH at room temperature in 2,2,2-trifluoroethanol (0.3ml). The mixture was stirred for 4 h at 50° C. The residual material waspurified by column chromatography (silica gel 40-60, hexane/ethylacetate 96:4) affording compound 35 (25 mg, 70% yield) as a thick oil.Characterization data of compound 35: ¹H NMR (CDCl₃/500 MHz): δ 6.12 (s,2H), 3.80 (s, 3H), 3.79 (s, 6H), 2.71-2.65 (m, 2H), 2.62-2.54 (m, 4H),2.55 (t, J=7.2 Hz, 1H), 1.83 (q, J=7.4 Hz, 2H), 1.59-1.53 (m, 2H),1.48-1.42 (m, 2H), 1.25 (t, J=7.4 Hz, 3H); ¹³C NMR (CDCl₃/125 MHz): δ159.1, 158.8, 111.6, 90.5, 55.7, 55.3, 51.4, 36.0, 31.6, 28.9, 27.6,24.2, 22.7, 22.3, 14.6, 14.1; HRMS (ESI): m/z calcd for C₁₈H₃₀O₃S₂[M+Na]⁺ 381.1529, found 381.1526.

Example 2 Process B; Reduction of the Thiol

An exemplary embodiment of the process of the invention is shown in thefollowing equation:

In Process B (also referred to as: “Method B”) the products obtainedaccording by process A were reduced by Et₃SiH as described hereinbelow,to thereby form a compound represented by Formula IV, as definedhereinabove.

Synthesis of Specific Compounds:

In exemplary procedures, “process A” was first performed, i.e. asolution of aldehyde (0.75 mmol), arene (0.25 mmol), ethanethiol (1.5mmol) and Cu(OTf)₂ (2.5 mol %) in 2,2,2-trifluoroethanol (0.75 mL), (1.5mmol) was stirred at the required temperature.

Upon completion, the reaction mixture was cooled to room temperature andtriethylsilane (0.75 mmol) was added and the reaction was stirred at 50°C. At the end of the reduction process, all volatiles were removed underreduced pressure and the crude residue purified over silica-gelchromatography affording the desired coupling product.

Compound 36:

Paraformaldehyde (22.5 mg, 0.75 mmol), Cu(OTf)₂ (2.2 mg, 2.5 mol %),ethanethiol (108 μl, 1.5 mmol) and 3,5-dimethoxyphenol (39 mg, 0.25mmol) were reacted according to method B. The mixture was stirred for 7h at 50° C. in sealed tube. After the addition of Et₃SiH (119 μl, 0.75mmol) the reaction was stirred for 4 h at 50° C. The residual materialwas purified by column chromatography (silica gel 40-60, hexane/ethylacetate 90:10) affording compound 36 (21.3 mg, 51% yield) as a whitesolid. Characterization data of compound 36: ¹H NMR (CDCl₃/400 MHz): δ6.10 (s, 1H), 6.05 (s, 1H), 3.79 (s, 3H), 3.75 (s, 3H), 2.04 (s, 3H);¹³C NMR (CDCl₃/100 MHz): δ 159.9, 159.1, 155.6, 106.9, 93.2, 91.3, 55.2,35.6, 33.5, 29.8; HRMS (ESI): m/z calcd for C₉H₁₂O₃[M+H]⁺ 169.0859,found 169.0858.

Compound 37:

Acetaldehyde (42 μl, 0.75 mmol), Cu(OTf)₂ (2.2 mg, 2.5 mol %),ethanethiol (108 μl, 1.5 mmol) and sesamol (34.5 mg, 0.25 mmol) werereacted according to method B. After the addition of Et₃SiH (116 μl,0.75 mmol) the reaction was stirred for 1.5 h at 50° C. The residualmaterial was purified by column chromatography (silica gel 40-60,hexane/ethyl acetate 90:10) affording compound 37 (34 mg, 81% yield) asa thick oil. Characterization data of compound 37: ¹H NMR (CDCl₃/400MHz): δ 6.62 (s, 1H), 6.39 (s, 1H), 5.87 (s, 2H), 4.85 (br s, OH), 2.54(q, J=7.5 Hz, 2H), 1.19 (t, J=7.5 Hz, 3H); ¹³C NMR (CDCl₃/100 MHz): δ147.6, 145.8, 141.4, 121.9, 108.6, 100.9, 98.1, 22.8, 14.4; HRMS (ESI):m/z calcd for C₉H₁₀O₃[M+H]⁺ 167.0703, found 167.0706.

Compound 38:

Isobutyrlaldehyde (46 μl, 0.75 mmol), Cu(OTf)₂ (2.2 mg, 2.5 mol %),ethanethiol (108 μl, 1.5 mmol) and 3,5-dimethylphenol (30.5 mg, 0.25mmol) were reacted according to method B. The mixture was stirred for 6h at 50° C. After the addition of Et₃SiH (116 μl, 0.75 mmol) thereaction was stirred for 3 h at 50° C. The residual material waspurified by column chromatography (silica gel 40-60, hexane/diethylether96:4) affording compound 38 (33 mg, 73% yield) as a colorless thick oil.Characterization data of compound 38: ¹H NMR (CDCl₃/400 MHz): δ 6.6 (s,1H), 6.46 (s, 1H), 4.6 (s, OH), 2.5 (d, J=7.3 Hz, 2H), 2.3 (s, 3H), 2.2(s, 3H), 1.9 (non, J=6.8 Hz, 1H), 0.96 (d, J=6.6 Hz, 6H); ¹³C NMR(CDCl₃/100 MHz): δ 153.8, 138.1, 136.1, 123.7, 123.3, 113.7, 35.0, 28.9,22.7, 20.9, 19.9; HRMS (ESI): m/z calcd for C₁₂H₁₈O [M+H]⁺ 179.1430,found 179.1429.

Compound 39-d₁:

Isobutyrlaldehyde (68 μl, 0.75 mmol), Cu(OTf)₂ (2.2 mg, 2.5 mol %),ethanethiol (108 μl, 1.5 mmol) and 2,6-dimethylphenol (30.5 mg, 0.25mmol) were reacted according to method B. The mixture was stirred for 4h at 50° C. After the addition of Et₃SiH (119 μl, 0.75 mmol) thereaction was stirred for 4 h at 50° C. The residual material waspurified by column chromatography (silica gel 40-60, hexane/ethylacetate 96:4) affording compound 39-d₁ (32 mg, 71% yield) as thickyellowish oil. Characterization data of compound 39-d₁: ¹H NMR(CDCl₃/500 MHz): δ 6.75 (s, 2H), 2.32 (d, J=7.1 Hz, 1H), 2.23 (s, 6H),1.78 (oct, J=6.6 Hz, 1H), 0.89 (d, J=6.6 Hz, 6H), 2.39-2.27 (m, 3H),2.19-2.08 (m, 2H), 1.96-1.93 (m, 1H), 1.89-1.84 (m, 3H), 1.73-1.67 (m,1H), 1.52-1.25 (m, 10H), 1.17 (q, J=7.2 Hz, 3H), 0.88-0.85 (m, 3H), 0.79(s, 3H); ¹³C NMR (CDCl₃/125 MHz): δ 150.1, 133.4, 129.2, 122.5, 44.2 (t,1H), 30.3, 22.4, 15.9; HRMS (ESI): m/z calcd for C₁₂H₁₇OD [M−H]⁺180.1493 found 180.1449.

Compound 40:

Isovalericaldehyde (82 μl, 0.75 mmol), Cu(OTf)₂ (2.2 mg, 2.5 mol %),ethanethiol (108 μl, 1.5 mmol) and 6-bromo-2-naphthol (55.75 mg, 0.25mmol) were reacted according to method B. The mixture was stirred for 6h at 50° C. After the addition of Et₃SiH (119 μl, 0.75 mmol) thereaction was stirred for 3 h at 50° C. The residual material waspurified by column chromatography (silica gel 40-60, hexane/diethylether95:5) affording compound 40 (57 mg, 78% yield) as a white solid.Characterization data of compound 40: ¹H NMR (CDCl₃/400 MHz): δ 7.91 (d,J=1.8 Hz, 1H), 7.77 (d, J=9.1 Hz, 1H), 7.53 (dd, J=2, 9.2 Hz, 1H), 7.51(d, J=9.2 Hz, 1H), 7.06 (d, J=8.9 Hz, 1H), 5.01 (br s, OH), 2.98 (m,2H), 1.74 (hep, J=6.5 Hz, 1H), 1.53-1.47 (m, 2H), 1.03 (d, J=6.7 Hz,6H); ¹³C NMR (CDCl₃/100 MHz): δ 150.5, 131.7, 130.7, 130.5, 129.5,126.6, 124.9, 121.1, 118.7, 116.8, 38.9, 28.6, 23.1, 22.6; HRMS (ESI):m/z calcd for C₁₅H₁₇BrO [M−H]⁺ 292.0457 and 294.0437, found 292.0457 and294.0434.

Compound 41:

Isobutylaldehyde (68 μl, 0.75 mmol), Cu(OTf)₂ (2.2 mg, 2.5 mol %),ethanethiol (108 μl, 1.5 mmol) and 2-naphthol (36 mg, 0.25 mmol) werereacted according to method B. The mixture was stirred for 6 h at 50° C.After the addition of Et₃SiH (116 μl, 0.75 mmol) the reaction wasstirred for 2 h at 50° C. The residual material was purified by columnchromatography (silica gel 40-60, hexane/ethyl acetate 96:4) affordingcompound 41 (44 mg, 87% yield) as a thick oil. Characterization data ofcompound 41: ¹H NMR (CDCl₃/400 MHz): δ 7.96 (d, J=8.6 Hz, 1H), 7.8 (d,J=8.2 Hz, 1H), 7.66 (d, J=8.8 Hz, 1H), 7.51 (ddd, J=1.4, 6.4, 8.1, 1H),7.36 (ddd, J=1.0, 6.8, 8.9 Hz, 1H), 7.09 (d, J=8.9 Hz, 1H), 5.01 (s,1H), 2.96 (d, J=7.5 Hz, 2H), 2.18-2.08 (m, 1H), 1.06 (d, J=6.6 Hz, 6H);¹³C NMR (CDCl₃/100 MHz): δ 150.9, 133.7, 129.5, 128.7, 127.8, 126.2,123.5, 123.0, 119.4, 117.7, 34.1, 29.5, 22.8; HRMS (ESI): m/z calcd forC₁₄H₁₆O [M−H]⁺ 199.1117, found 199.1116.

Compound 42:

Isobutyrlaldehyde (68 mg, 0.75 mmol), Cu(OTf)₂ (2.2 mg, 2.5 mol %),ethanethiol (108 μl, 1.5 mmol) and 6-methoxy-2-naphthol (43.5 mg, 0.25mmol) were reacted according to method B. The mixture was stirred for 4h at 50° C. in sealed tube. After the addition of Et₃SiH (116 μl, 0.75mmol) the reaction was stirred for 4 h at 50° C. The residual materialwas purified by column chromatography (silica gel 40-60, hexane/ethylacetate 95:5) affording compound 42 (45 mg, 78% yield) as a thick oil.Characterization data of compound 42: ¹H NMR (CDCl₃/400 MHz): δ 7.82 (d,J=9.2 Hz, 1H), 7.52 (d, J=8.7 Hz, 1H), 7.15 (dd, J=2.7, 9.1 Hz, 1H),7.10 (d, J=2.6 Hz, 1H), 7.05 (d, J=8.7 Hz, 1H), 4.74 (s, OH), 3.90 (s,3H), 2.89 (d, J=7.2 Hz, 2H), 2.05 (h, J=6.9 Hz, 1H), 1.00 (d, J=6.6 Hz,6H); ¹³C NMR (CDCl₃/100 MHz): δ 155.5, 149.4, 130.4, 128.9, 126.3,125.1, 119.8, 118.7, 118.1, 106.8, 55.3, 34.2, 29.5, 22.8; HRMS (ESI):m/z calcd for C₁₅H₁₈O₂[M+H]⁺ 229.1223, found 229.1223.

Compound 43:

Trimethylacetaldehyde (81 μl, 0.75 mmol), Cu(OTf)₂ (2.2 mg, 2.5 mol %),ethanethiol (108 μl, 1.5 mmol) and 3,5-dimethoxyphenol (38.5 mg, 0.25mmol) were reacted according to method B. The mixture was stirred for 12h at 50° C. After the addition of Et₃SiH (116 μl, 0.75 mmol) thereaction was stirred for 5 h at 50° C. The residual material waspurified by column chromatography (silica gel 40-60, hexane/ethylacetate 90:10) affording compound 43 (37 mg, 70% yield) as a whitesolid. Characterization data of compound 43: ¹H NMR (CDCl₃/400 MHz): δ6.10 (d, J=2.3, 1H), 6.06 (d, J=2.3 Hz, 1H), 4.94 (br s, OH), 3.76 (s,3H), 3.74 (s, 3H), 2.49 (s, 2H), 0.94 (s, 9H); ¹³C NMR (CDCl₃/100 MHz):δ 159.9, 159.1, 155.6, 106.9, 93.2, 91.3, 55.2, 35.6, 33.5, 29.8; HRMS(ESI): m/z calcd for C₁₃H₂₀O₃ [M+H]⁺ 225.1485, found 225.1503.

Compound 44:

Nonalaldehyde (129 μl, 0.75 mmol), Cu(OTf)₂ (2.2 mg, 2.5 mol %),ethanethiol (108 μl, 1.5 mmol) and 3,4,5-trimethoxyphenol (46 mg, 0.25mmol) were reacted according to method B. The mixture was stirred for 7h at 50° C. After the addition of Et₃SiH (116 μl, 0.75 mmol) thereaction was stirred for 4 h at 50° C. The residual material waspurified by column chromatography (silica gel 40-60, hexane/ethylacetate 85:15) affording compound 44 (48 mg, 62% yield) as a thick oil.Characterization data of compound 44: ¹H NMR (CDCl₃/400 MHz): δ 6.19 (s,1H), 3.87 (s, 3H), 3.80 (s, 3H), 3.75 (s, 3H), 2.52 (t, J=7.9 Hz, 2H),1.53-1.45 (m, 2H), 1.35-1.20 (m, 12H), 0.87 (t, J=7.0 Hz, 3H); ¹³C NMR(CDCl₃/100 MHz): δ 152.4, 151.5, 149.8, 136.1, 114.6, 96.0, 61.2, 61.0,55.9, 31.9, 30.2, 29.9, 29.6, 29.6, 29.4, 23.7, 22.7, 14.1; HRMS (ESI):m/z calcd for C₁₈H₃₀O₄[M+H]⁺ 311.2217, found

311.2213.

Compound 45:

4-chlorobenzaldehyde (130.5 mg, 0.75 mmol), Cu(OTf)₂ (2.2 mg, 2.5 mol%), ethanethiol (108 μl, 1.5 mmol) and sesamol (34.5 mg, 0.25 mmol) werereacted according to method B. The mixture was stirred for 4 h at 50° C.After the addition of Et₃SiH (116 μl, 0.75 mmol) the reaction wasstirred for 3 h at 50° C. The residual material was purified by columnchromatography (silica gel 40-60, hexane/ethyl acetate 90:10) affordingcompound 45 (60 mg, 91% yield) as a thick oil. Characterization data ofcompound 45: ¹H NMR (CDCl₃/400 MHz): δ 7.26-7.23 (m, 2H), 7.15-7.12 (m,2H), 6.56 (s, 1H), 6.39 (s, 1H), 5.88 (s, 2H), 3.85 (s, 2H); ¹³C NMR(CDCl₃/100 MHz): δ 147.9, 146.7, 141.6, 138.8, 132.0, 129.9, 118.6,110.0, 101.1, 98.6, 35.3; HRMS (ESI): m/z calcd for C₁₄H₁₁ClO₃ [M+H]⁺263.0469, found 263.0474.

Compound 46:

7-hyroxycitronellal (140 μl, 0.75 mmol), Cu(OTf)₂ (2.2 mg, 2.5 mol %),ethanethiol (108 μl, 1.5 mmol) and 1,3,5-trimethoxybenzene (42 mg, 0.25mmol) were reacted according to method B. The mixture was stirred for 2h at rt. After the addition of Et₃SiH (116 μl, 0.75 mmol) the reactionwas stirred for 1 h at room temperature. The residual material waspurified by column chromatography (silica gel 40-60, hexane/ethylacetate 80:20) affording compound 46 (64 mg, 79% yield) as a thick oil.Characterization data of compound 46: ¹H NMR (CDCl₃/400 MHz): δ 6.13 (s,2H), 3.80 (s, 3H), 6.79 (s, 6H), 2.60-2.48 (m, 2H), 1.49-1.24 (m, 9H),1.21 (s, 6H), 0.93 (d, J=6.2, Hz, 3H); ¹³C NMR (CDCl₃/100 MHz): δ 159.0,158.7, 112.3, 90.6, 71.1, 55.7, 55.3, 44.4, 37.3, 36.6, 32.9, 29.3,29.2, 21.6, 20.1, 19.7; HRMS (ESI): m/z calcd for C₁₉H₃₂O₄[M+H]⁺325.2373 found 325.2363.

Compound 47:

3-((7-chloro-3,7 dimethyloctyl)oxy)benzaldehyde (87 mg, 0.29 mmol),Cu(OTf)₂ (2.2 mg, 2.5 mol %), ethanethiol (43 μl, 0.6 mmol) and1,3,5-trimethoxybenzne (33.6 mg, 0.2 mmol) were reacted according tomethod B. The mixture was stirred for 0.5 h at 50° C. After the additionof Et₃SiH (119 μl, 0.75 mmol) the reaction was stirred for 4 h at 50° C.The residual material was purified by column chromatography (silica gel40-60, hexane/ethyl acetate 95:5) affording compound 47 (81 mg, 90%yield) as a thick oil. Characterization data of compound 47: ¹H NMR(CDCl₃/400 MHz): δ 7.13 (t, J=8.0 Hz, 1H), 6.82 (m, 2H), 6.68 (d, J=8.0Hz, 1H), 6.17 (s, 2H), 3.97 (q, J=6.4 Hz, 2H), 3.93 (s, 2H), 3.82 (s,3H), 3.80 (s, 6H), 1.87-1.79 (m, 1H), 1.76-1.68 (m, 2H), 1.59 (s, 6H),1.56-1.51 (m, 2H), 1.43-1.35 (m, 1H), 1.27-1.18 (m, 2H), 0.97 (d, J=6.3Hz, 3H); ¹³C NMR (CDCl₃/100 MHz): δ 159.7, 158.9, 143.9, 128.8, 120.8,114.9, 111.3, 110.1, 90.7, 71.3, 65.9, 55.7, 55.4, 46.3, 37.1, 36.3,32.5, 29.8, 28.9, 28.4, 22.5, 19.6; HRMS (ESI): m/z calcd for C₂₆H₃₇ClO₄[M+H]⁺ 449.2453 found 449.2449.

Compound 48:

Prepared according to method B with 3-(allyloxy)benzaldehyde (81 mg, 0.5mmol), Cu(OTf)₂ (2.2 mg, 2.5 mol %), ethanethiol (72 μl, 1.0 mmol) and1,3,5-trimethoxybenzene (42 mg, 0.25 mmol). The mixture was stirred for1.5 h at rt. After the addition of Et₃SiH (116 μl, 0.75 mmol) thereaction was stirred at room temperature for 0.5 h. The residualmaterial was purified by column chromatography (silica gel 40-60,hexane/ethyl acetate 93:7) to obtain compound 48 (74 mg, 94% yield) as athick oil. Characterization data of compound 48: ¹H NMR (CDCl₃/400 MHz):δ 7.12 (d, J=7.8 Hz, 1H), 6.84 (d, J=7.8 Hz, 1H), 6.82 (s, 1H), 6.68(dd, J=8.3, 1.8 Hz, 2H), 6.15 (s, 2H), 6.05 (ddt, J=17.0, 10.7, 5.2,1H), 5.39 (dd, J=17.0, 1.2 Hz, 1H), 5.39 (dd, J=10.5, 0.7 Hz, 1H), 4.49(d, J=10.5, 5.2, 2H), 3.91 (s, 2H), 3.81 (s, 3H), 3.79 (s, 6H); ¹³C NMR(CDCl₃/100 MHz): δ 159.7, 158.9, 158.5, 144.0, 133.7, 128.8, 121.2,117.5, 115.1, 111.3, 110.0, 90.6, 68.7, 55.7, 55.4, 28.3; HRMS (ESI):m/z calcd for C₁₉H₂₂O₄[M+H]⁺ 337.1410 found 337.1406.

Compound 49a:

4-cyanobenzaldehyde (98 mg, 0.75 mmol), Cu(OTf)₂ (2.2 mg, 2.5 mol %),ethanethiol (108 μl, 1.5 mmol) and 1,3,5-trimethoxybenzene (42 mg, 0.25mmol) were reacted according to method B. The mixture was stirred at 50°C. for 3 h. After the addition of Et₃SiH (116 μl, 0.75 mmol) thereaction was stirred for 2 h at 50° C. The residual material waspurified by column chromatography (silica gel 40-60, hexane/ethylacetate 90:10) affording compound 49a (69 mg, 97% yield) as a whitesolid. Characterization data of compound 49a: ¹H NMR (CDCl₃/400 MHz): δ7.48 (d, J=8.4 Hz, 2H), 7.31 (d, J=8.3 Hz, 2H), 6.15 (s, 2H), 3.96 (s,2H), 3.81 (s, 3H), 3.78 (s, 3H); ¹³C NMR (CDCl₃/100 MHz): δ 160.2,158.8, 148.2, 131.8, 129.2, 119.5, 108.9, 108.5, 90.6, 55.7, 55.4, 28.7.

Compound 49:

Isobutyraldehyde (97 μl, 1.06 mmol), Cu(OTf)₂ (3.2 mg, 2.5 mol %),ethanethiol (153 μl, 2.12 mmol) and4-(2,4,6-trimethoxybenzyl)benzonitrile (100 mg, 0.35 mmol) were reactedaccording to method B. The mixture was stirred for 10 h at 50° C. Afterthe addition of Et₃SiH (116 μl, 0.75 mmol) the reaction was stirred for4 h at 50° C. The residual material was purified by columnchromatography (silica gel 40-60, hexane/ethyl acetate 93:7) affordingcompound 49 (51 mg, 43% yield) as a thick oil. Characterization data ofcompound 49: ¹H NMR (CDCl₃/400 MHz): δ 7.49 (d, J=8.1 Hz, 2H), 7.27 (d,J=8.1 Hz, 2H), 6.31 (s, 1H), 4.01 (s, 2H), 3.82 (s, 3H), 3.76 (s, 3H),3.58 (s, 3H), 2.46 (d, J=7.3 Hz, 2H), 1.89 (non, J=6.7 Hz, 1H), 0.87 (d,J=6.7 Hz, 6H); ¹³C NMR (CDCl₃/100 MHz): δ 158.5, 158.2, 156.8, 148.2,131.9, 129.0, 119.4, 116.0, 112.8, 109.1, 91.7, 61.5, 55.6, 55.5, 32.6,29.7, 28.8, 22.6; HRMS (ESI): m/z calcd for C₂₁H₂₅NO₃ [M+Na]⁺ 340.1907found 340.1900.

Compound 50:

Benzaldehyde (77 μl, 0.75 mmol), Cu(OTf)₂ (2.2 mg, 2.5 mol %),ethanethiol (108 μl, 1.5 mmol) and β-estradiol (68 mg, 0.25 mmol) werereacted according to method B. The mixture was stirred for 8 h at 50° C.After the addition of Et₃SiH (116 μl, 0.75 mmol) the reaction wasstirred for 4 h at 50° C. The residual material was purified by columnchromatography (silica gel 40-60, hexane/ethyl acetate 85:15) affordingcompound 50 (77 mg, 85% yield) as a thick oil. Characterization data ofcompound 50: ¹H NMR (CDCl₃/500 MHz): δ 7.31-7.18 (m, 5H), 7.05 (s, 1H),6.52 (s, 1H), 4.00-3.91 (m, 2H), 3.73 (t, J=8.4 Hz, 1H), 2.85-2.74 (m,2H), 2.28-2.24 (m, 1H), 2.20-2.07 (m, 2H), 1.96-1.82 (m, 2H), 1.73-1.66(m, 1H), 1.52-1.15 (m, 7H), 0.78 (s, 3H); ¹³C NMR (CDCl₃/100 MHz): δ151.6, 140.4, 136.4, 132.7, 130.1, 128.6, 128.6, 128.0, 128.0, 126.2,124.2, 115.8, 82.0, 50.0, 44.0, 43.3, 38.9, 36.7, 36.4, 30.6, 29.3,27.3, 26.4, 23.2, 11.3; [α]_(D) ^(22.8): +54.5 (c=0.55, CHCl₃); HRMS(ESI): m/z calcd for C₂₅H₃₀O₂[M+Na]⁺ 385.2138 found 385.2137.

Compound 51:

Isobutyraldehyde (68 μl, 0.75 mmol), Cu(OTf)₂ (2.2 mg, 2.5 mol %),ethanethiol (108 μl, 1.5 mmol) and β-estradiol (68 mg, 0.25 mmol) werereacted according to method B. The mixture was stirred for 8 h at 50° C.After the addition of Et₃SiH (116 μl, 0.75 mmol) the reaction wasstirred for 4 h at 50° C. The residual material was purified by columnchromatography (silica gel 40-60, hexane/ethyl acetate 80:20) affordingcompound 51 (55 mg, 67% yield) as a with solid. Characterization data ofcompound 51: ¹H NMR (CDCl₃/400 MHz): δ 6.98 (s, 1H), 6.49 (s, 1H), 4.54(s, 1H), 3.74 (t, J=8.5 Hz, 1H), 2.86-2.75 (m, 2H), 2.45-2.40 (m, 2H),2.35-2.29 (m, 1H), 2.20-2.08 (m, 2H), 1.97-1.83 (m, 3H), 1.74-1.66 (m,1H), 1.53-1.28 (m, 7H), 1.23-1.15 (m, 1H), 0.93 (d, J=6.6 Hz 6H), 0.78(s, 3H); ¹³C NMR (CDCl₃/100 MHz): δ 151.4, 135.5, 132.3, 128.2, 124.7,115.2, 82.0, 50.1, 44.0, 43.3, 39.3, 38.9, 36.8, 30.6, 29.2, 29.1, 27.3,26.4, 23.2, 22.7, 11.1; [α]_(D) ^(22.8): +70.8 (c=0.57, CHCl₃); HRMS(ESI): m/z calcd for C₂₅H₃₀O₂[M+H]⁺ 363.2319 found 363.2318.

Compound 52:

Benzaldehyde (25.5 μl, 0.25 mmol), Cu(OTf)₂ (2.2 mg, 2.5 mol %),ethanethiol (21.6 μl, 0.3 mmol, 1.2 equiv) and 1,3,5-trimethoxybenene(68 mg, 0.25 mmol). The mixture was stirred for 4 h at 50° C. After theaddition of Et₃SiH (116 μl, 0.75 mmol) the reaction was stirred for 2 hat 50° C. The residual material was purified by column chromatography(silica gel 40-60, hexane/ethyl acetate 95:5) affording compound 52 (52mg, 80% yield) as a thick oil. Characterization data of compound 52: ¹HNMR (CDCl₃/500 MHz): δ 7.17-7.10 (m, 4H), 7.04-7.01 (m, 1H), 6.07 (s,2H), 3.85 (s, 2H), 3.72 (s, 3H), 3.70 (s, 3H); ¹³C NMR (CDCl₃/100 MHz):δ 159.7, 158.9, 142.3, 128.4, 128.0, 125.3, 110.3, 90.6, 55.7, 55.3,28.3; HRMS (ESI): m/z calcd for C₁₆H₁₈O₃[M+H]⁺ 259.1329 found 259.1328.

Compound 53:

To a stirred solution of compound 23 (284 mg, 1 mmol) in2,2,2-trifluoroethanol (2 ml) was added H₂O₂ (102 μl, 30% in H₂O, 1mmol) at 0° C. The mixture was stirred for 1 h, all volatiles wereremoved under reduced pressure and the residual crude material waspurified by column chromatography (silica gel 40-60, ethyl acetate)affording compound 53 (240 mg, 80% yield) as a thick oil.Characterization data of compound 53: ¹H NMR (CDCl₃/400 MHz): δ 6.12 (s,1H), 6.10 (s, 1H), 4.01 (d, J=10.7 Hz, 1H), 3.76 (s, 3H), 3.75 (s, 3H),3.73 (s, 3H), 2.93-2.83 (m, 1H), 2.61-2.54 (m, 1H), 2.47-2.40 (m, 1H),1.25 (t, J=7.5 Hz, 3H), 1.09 (d, J=6.6 Hz, 3H), 0.75 (d, J=6.6 Hz, 3H);¹³C NMR (CDCl₃/100 MHz): δ 160.9, 160.8, 159.6, 103.2, 91.4, 90.7, 65.1,55.9, 55.7, 55.2, 45.6, 28.0, 25.4, 22.4, 21.9, 7.8; HRMS (ESI): m/zcalcd for C₁₅H₂₄O₄S [M+Na]⁺ 323.1288 found 323.1285.

One-Pot Follow-Up Procedure to Compound 53:

Isobutyrlaldehyde (68 μl, 0.75 mmol), Cu(OTf)₂ (2.2 mg, 2.5 mol %),ethanethiol (108 μl, 1.5 mmol) and 1,3,5-trimethoxybenzene (42 mg, 0.25mmol) were reacted according to method A. The mixture was stirred insealed tube at 50° C. for 2 h. Then the mixture was cooled to 0° C.,H₂O₂ (51 μl, 30% in H₂O, 0.5 mmol) was added slowly. And the reactionwas further stirred for 1 h. After removal of all volatiles underreduced pressure, the residual crude material was purified by columnchromatography (silica gel 40-60, ethyl acetate) affording compound 53(41 mg, 55% yield) as a thick oil.

Compound 54:

A solution of sulfoxide 53 (60 mg, 0.2 mmol), allyltrimethylsilane (95ml, 0.6 mmol) and Cu(OTf)₂ (1.8 mg, 2.5 mol %) in 2,2,2-trifuloroethanol(0.4 ml) were stirred at room temperature for 2 h. After completion ofthe reaction, as indicated by TLC analysis, all volatiles were removedunder reduced pressure and the residual crude material was purified bycolumn chromatography (silica gel 40-60, ethyl acetate/hexane 97:3)affording compound 54 (41 mg, 78% yield) as a thick oil.Characterization data of compound 54: ¹H NMR (CDCl₃/400 MHz): δ 6.11 (s,2H), 5.61-5.51 (m, 1H), 4.84 (d, J=17.0 Hz, 1H), 4.73 (d, J=10.0 Hz,1H), 3.80 (s, 3H), 3.75 (s, 6H), 2.95 (dt, J=5.4, 4.9 Hz, 1H), 2.62-2.54(m, 1H), 2.48-2.42 (m, 1H), 2.16-2.07 (m, 1H), 1.01 (d, J=6.6 Hz, 3H),0.75 (d, J=6.7 Hz, 3H); ¹³C NMR (CDCl₃/100 MHz): δ 159.7, 158.9, 139.5,113.7, 113.4, 91.2, 90.7, 56.1, 55.1, 42.4, 35.7, 30.8, 21.9; HRMS(ESI): m/z calcd for C₁₆H₂₄O₃[M+Na]⁺ 265.1798 found 265.1797.

Compound 3a:

To a stirred solution of compound 3 (284 mg, 1 mmol) in2,2,2-trifluoroethanol (2 ml) was added H₂O₂ (102 μl, 30% in H₂O, 1mmol) at 0° C. The mixture was stirred for 1 h, all volatiles wereremoved under reduced pressure and the residual crude material waspurified by column chromatography (silica gel 40-60, ethyl acetate)affording compound 3a (72 mg, 94% yield) as a thick oil.Characterization data of compound 3a: ¹H NMR (CDCl₃/500 MHz): δ7.39-7.38 (m, 2H), 7.32-7.30 (m, 2H), 6.92-6.88 (m, 4H), 4.73 (s, 1H),3.79 (s, 3H), 3.77 (s, 3H), 2.57-2.49 (m, 1H), 2.46-2.39 (m, 1H), 1.27(t, J=7.5 Hz, 3H); ¹³C NMR (CDCl₃/125 MHz): δ 159.1, 159.4, 130.4,129.7, 128.1, 127.4, 114.6, 114.2, 70.3, 55.3, 55.3, 44.1; HRMS (ESI):m/z calcd for C₁₇H₂₀O₃S [M+Na]⁺ 327.1025 found 327.1025.

Compound 55:

A solution of compound 3a (131 mg, 0.43 mmol) was treated with1,3,5-trimethoxybenzene (145 ml, 0.86 mmol) at rt in trifuloroethanol(0.8 ml), followed by addition of Cu(OTf)₂ (4 mg, 2.5 mol %). Themixture was stirred for 0.5 h at rt. The residual material was purifiedby column chromatography (silica gel 40-60, hexane/ethyl acetate 93:7)affording compound 55 (151 mg, 89% yield) as a thick pink oil.Characterization data of compound 55: ¹H NMR (CDCl₃/500 MHz): δ 7.14 (d,J=8.1 Hz, 4H), 6.80 (d, J=8.7 Hz, 4H), 6.18 (s, 2H), 5.99 (s, 1H), 3.82(s, 3H), 3.80 (s, 6H), 3.63 (s, 6H); ¹³C NMR (CDCl₃/125 MHz): δ 159.9,159.1, 157.4, 136.6, 130.0, 114.1, 113.0, 91.7, 55.8, 55.3, 55.2, 43.6;HRMS (ESI): m/z calcd for C₂₄H₂₆O₅[M+Na]⁺ 395.1853 found 395.1853.

Compound 56:

A solution of compound 3a (76 mg, 0.25 mmol), azidotrimethylsilane (130ml, 1 mmol) and Cu(OTf)₂ (2.2 mg, 2.5 mol %) in 2,2,2-trifluoroethanol(0.75 ml) was stirred at room temperature for 1.5 h. The residual crudematerial was purified by column chromatography (silica gel 40-60,hexane/ethyl acetate 95:5) to obtain compound 56 (59 mg, 87% yield) as athick colorless oil. Characterization data of compound 56: ¹H NMR(CDCl₃/400 MHz): δ 7.23 (d, J=8.5 Hz, 4H), 6.90 (d, J=8.5 Hz, 4H), 5.65(s, 1H), 3.81 (s, 6H); ¹³C NMR (CDCl₃/100 MHz): δ 159.3, 132.1, 128.6,114.0, 67.7, 55.3; HRMS (ESI): m/z calcd for C₁₅H₁₅N₃O₂ [M+Na]⁺ 292.1056found 292.1055.

Example 3 Exploring the Role of the Thiol in the Synthesis Route

General:

Scheme 2 presents exemplary electrophilic aromatic substitution ofaldehydes and thionium ions following mixing 2-naphthol (1a in scheme 2)with an excess of isobutyraldehyde (2a in scheme 2) under acid-catalyzedconditions (Cu(OTf)₂ (5 mol %), 2,2,2-trifluoroethanol, roomtemperature) produced a complex reaction mixture, with naphthofuransbeing the major products (28% and 14% yields, respectively):

In exemplary procedure, a solution of isobutylaldehyde (68 μl, 0.75mmol) was treated with Cu(OTf)₂ (2.2 mg, 2.5 mol %) at rt intrifuloroethanol (0.75 ml), followed by addition of 2-naphthol (36 mg,0.25 mmol). The mixture was stirred for 10 h at 60° C. The residualmaterial was purified by column chromatography (silica gel 40-60,hexane/ether 98:2) to obtain compound 3 in scheme 2 (also referred to as“RP_984”) (13.7 mg, 28% yield) as white solid.

Compound A1′ and A2′:

Characterization data of compound 3 (referred to as: “A1′”): ¹H NMR(CDCl₃/400 MHz): δ 7.80 (d, J=8.1 Hz, 1H), 7.68 (d, J=8.7 Hz, 1H), 7.55(d, J=8.2 Hz, 1H), 7.46 (t, J=7.5 Hz, 1H), 7.29 (t, J=7.5 Hz, 1H), 7.08(d, J=8.7 Hz, 1H), 3.29 (s, 2H), 1.57 (s, 6H); ¹³C NMR (CDCl₃/100 MHz):δ 156.2, 131.2, 129.0, 128.9, 128.7, 126.6, 122.6, 122.6, 118.2, 112.4,87.5, 41.8, 28.6; HRMS (ESI): m/z calcd for C₁₄H₁₄O [M+H]⁺ 199.1117,found 199.1115.

Control Experiment—The Disassemble ofEthyl(phenyl(2,4,6-trimethoxyphenyl)methyl)sulfane 6 to Dithioacetal 6aand 1,3,5-trimethoxybenzene 1d.

Procedure:

A solution of compound 6 as described hereinbelow (40 mg, 0.125 mmol),ethanethiol (18 μl, 0.25 mmol) and Cu(OTf)₂ (1.1 mg, 2.5 mol %) in2,2,2-trifluoroethanol (0.375 ml) was stirred for 16 h at 50° C. Theprocess is shown in Scheme 2a below.

Characterization data of compound 4 (referred to as “A2′”): ¹H NMR(CDCl₃/400 MHz): δ 7.73 (s, 2H), 7.63 (d, J=8.8 Hz, 2H), 7.44 (s, 4H),7.02 (d, J=8.8 Hz, 2H), 3.69 (d, J=10.7 Hz, 1H), 3.21 (s, 4H), 2.75-2.65(m, 1H), 1.53 (s, 6H), 1.52 (s, 6H), 0.97 (d, J=6.4 Hz, 6H); ¹³C NMR(CDCl₃/100 MHz): δ 155.8, 139.1, 129.7, 129.2, 128.6, 127.5, 127.2,122.8, 118.1, 112.3, 87.4, 60.5, 41.8, 31.4, 28.6, 22.0; HRMS (ESI): m/zcalcd for C₃₂H₃₄O₂[M+H]⁺ 451.2636, found 451.2636.

This picture changed completely when the reaction was performed in thepresence of ethanethiol (e.g., 3 equiv), leading to a Pummerer typereaction: as demonstrated in scheme 2, the isobuyraldehyde is protectedas a dithioacetal that transforms under the acidic conditions to anactive thionium ion species that reacts with naphthols (designated as“1a” or “1b” in Scheme 2), affording benzylsulfides (5a and 5b in Scheme2) in 87% and 98% isolated yields, respectively.

Example 4 Synthesis Summary with Various Primary Alkyl Groups

The generality of the disclosed alkylation protocol was examined and theresults are described hereinbelow.

The method enables a direct entry to both linear and branched primaryalkyl substituents. Alkyl groups such as methyl (product B1, 51% yield),ethyl (B2, 81%), isobutyl (B3, 73% and B4, 78%), isopentyl (B5, 87% andB6, 78%) neopentyl (B7, 70%) and octanyl (B8, 63%) were installed inhigh chemo- and regioselectivity. Importantly, functional groups thatare incompatible with the Friedel-Crafts reaction or are sensitivetoward reduction, such as primary alkyl bromide (B9, 62%), tertiaryalkyl chloride (B10, 90%), tertiary alcohols (B11, B12; 85%, 42%,respectively) and aromatic nitrile (B13, 70%) were not affected.Finally, an isotope labeled alkyl group can be introduced by usingEt₃SiD as the reducing agent, affording B3-d₁ in 71%. B13 refers totwo-step synthesis: the first is benzylation and the second isalkylation.

Example 5 The Reaction in Aqueous Solutions

Contrary to the classic Friedel-Crafts alkylation, which requiresanhydrous conditions, the electrophilic aromatic substitution asdisclosed herein can be carried out in water, as exemplified for thecoupling of glutaraldehyde (scheme 3, 2b, 25% v/v in H₂O), whichprobably transforms to thionium ion (designated as “I”) before reactingwith arene (designated as “1c”) to afford dithioacetal 32 in moderate58% yield (Scheme 3).

Although the invention has been described in conjunction with specificembodiments thereof, it is evident that many alternatives, modificationsand variations will be apparent to those skilled in the art.Accordingly, it is intended to embrace all such alternatives,modifications and variations that fall within the spirit and broad scopeof the appended claims.

All publications, patents and patent applications mentioned in thisspecification are herein incorporated in their entirety by referenceinto the specification, to the same extent as if each individualpublication, patent or patent application was specifically andindividually indicated to be incorporated herein by reference. Inaddition, citation or identification of any reference in thisapplication shall not be construed as an admission that such referenceis available as prior art to the present invention. To the extent thatsection headings are used, they should not be construed as necessarilylimiting.

What is claimed is:
 1. A process comprising: reacting a compound havingFormula II:

with a compound having Formula III:

and with R₃SH in the presence of an acidic catalyst and a suitablesolvent, thereby forming a compound having Formula I:

wherein: R₁ is (C)_(n) or aryl, wherein n is between 1 to 20; R₂represents 0 to 5 substituents, wherein, in each occurrence, eachsubstituent is independently selected from the group consisting of:alkyl, alkenyl, alkynyl, cycloalkyl, heteroalicyclic, aryl, heteroaryl,hydroxy, alkoxy, aryloxy, thiohydroxy, thioalkoxy, thioaryloxy, halide,amine, amide, carbonyl, thiocarbonyl, carboxy, thiocarboxy, epoxide,sulfonate, sulfonyl, sulfinyl, sulfonamide, nitro, nitrile, isonitrile,thiirane, aziridine, nitroso, hydrazine, sulfate, azide, phosphonyl,phosphinyl, urea, thiourea, carbamyl and thiocarbamyl, or thesubstituents are joined together so as to form a fused ring systemcontaining up to three 6-member carbocyclic, each being substituted ornon-substituted; R₃ is selected from alkyl, aryl, alkoxy, aryloxy,carbonyl, carboxy, substituted or non-substituted; and R₄, R₅, and R₆are each independently selected from the group consisting of: hydrogen,alkyl, alkenyl, alkynyl, cycloalkyl, heteroalicyclic, aryl, heteroaryl,hydroxy, alkoxy, aryloxy, thiohydroxy, thioalkoxy, thioaryloxy, halide,amine, amide, carbonyl, thiocarbonyl, carboxy, thiocarboxy, epoxide,sulfonate, sulfonyl, sulfinyl, sulfonamide, nitro, nitrile, isonitrile,thiirane, aziridine, nitroso, hydrazine, sulfate, azide, phosphonyl,phosphinyl, urea, thiourea, carbamyl and thiocarbamyl, the processfurther comprising a subsequent step of reacting said compound havingFormula I with a reducing agent, thereby forming the compound havingFormula IV:


2. The process of claim 1, wherein R₃ is ethyl.
 3. The process of claim1, wherein said acidic catalyst is one or more Lewis acid selected fromthe group consisting of: CuCl₂, Sc(OTf)₃, Fe(OTf)₃, In(OTf)₃, BF3.OEt₂,and Cu(OTf)₂.
 4. The process of claim 1, wherein said acidic catalyst isone or more Brønsted acids selected from the group consisting of:Triflic acid (TfOH), para-toluenesulfonic acid, and trifluoroaceticacid.
 5. The process of claim 1, wherein said suitable solvent is apolar solvent selected from the group consisting of: acetonitrile,nitromethane, and 2,2,2-trifluoroethanol (TFE), hexafluoroisopropanol(HFIP) or a mixture thereof.
 6. The process of claim 1, characterized byat least 30% yield of the compound having Formula I.
 7. The process ofclaim 1, wherein said reducing agent is a silane.
 8. The process ofclaim 7, wherein said silane is Et₃SiH.